The Clinical Utility of Thrombelastography in Guiding Prophylaxis of Venous Thromboembolism Following Trauma (VTEPX)

An Evaluation of the Clinical Utility of Thrombelastography (TEG) in Guiding Low Molecular Weight Heparin (LMWH) and Antiplatelet Prophylaxis of Venous Thromboembolism (VTE) Following Trauma

This study plans to learn more about how to prevent blood clots in the veins of your extremities. You are at risk of forming these clots after a major injury and when you have had surgery and are hospitalized on bed rest.

Usually, patients in the SICU at Denver Health who are at risk for blood clots receive preventative treatment with a FDA-approved medicine called Fragmin. Fragmin is intended to prevent blood clots from forming but, with the way it is generally used, some patients may still develop blood clots. All patients treated with Fragmin to prevent blood clots at Denver Health, currently receive the same Fragmin dose. This treatment is called the "standard of care".

So far, in the US, there has not been a commonly available test that can tell us:

• if the standard dose of Fragmin is enough to prevent blood clots for everyone, or
• if different patients need different doses, or
• if other blood clot preventing medicines, that work in a different way, should be used in addition to Fragmin.

The ability of your blood to clot and the strength of the clot formed can be described by a FDA-approved blood test called thrombelastography, referred to as TEG. TEG may provide us with answers to each of the questions above. Our preliminary data indicate that it is helpful in assessing both clotting and bleeding tendencies and may prove useful in guiding treatment for the prevention of blood clots.

The aim of this study is to determine if a treatment plan using Fragmin, and, if indicated, one or two additional FDA-approved medicines called anti-platelet drugs, guided by the results of TEG testing, may be better at preventing blood clots than our current standard of care.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Dalteparin sodium; Drug: Dalteparin sodium/aspirin

Detailed Description

This preliminary/pilot study involves a prospective, randomized, open-label, parallel group comparison of Denver Health's current standard of care for prevention of venous thromboembolism (VTE), commonly known as blood clots, using LMWH (Fragmin) 5000IU subcutaneously daily, with a thrombelastography (TEG)-guided, algorithm-based, individualized regimen of LMWH (Fragmin) plus/minus anti-platelet therapy (aspirin) guided by platelet mapping, in patients admitted to the SICU following trauma.

Approximately 50 trauma patients for whom prevention of VTE with LMWH is indicated, will be enrolled over a six month period.

The specific aims of this study are as follows:

1. To determine the incidence of, and to characterize, hypercoagulability using TEG and conventional clinical coagulation testing (APTT, INR), Antithrombin III levels and Protein C activity.

2. In the group of patients receiving LMWH (Fragmin) therapy alone for prevention of VTE:

   1. to assess the anticoagulant effect of standard LMWH (Fragmin) dosing (5000IU subcutaneously once daily) using TEG and Anti-Factor Xa level measurement, and
   2. to determine the extent of correlation of relevant TEG parameters with measured Anti-Factor Xa levels (U/ml).
3. To assess whether TEG is a useful clinical tool for monitoring and optimizing prophylactic LMWH (Fragmin) therapy and for identifying the need for anti-platelet therapy to minimize the risk of VTE in these patients.
4. To evaluate the clinical utility of platelet mapping for guiding anti-platelet therapy in those patients for whom it is indicated by TEG results.
5. To determine the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in each randomized group and in the subgroup receiving anti-platelet therapy in addition to LMWH (Fragmin) for prevention of VTE.

The overall aim is to utilize the above data to evaluate a) the adequacy of our standard Fragmin dosing regimen (5000IU subcutaneously once daily) alone for prevention of VTE in our trauma/SICU patients, b) the need for anti-platelet agents in addition to LMWH (Fragmin) for prevention of VTE in our population, and c) to validate/further develop the TEG-guided algorithm for optimal prophylaxis of VTE using LMWH (Fragmin) plus/minus anti-platelet therapy guided by platelet mapping.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80203
      • Denver Health Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age at least 18 years,
• blunt or penetrating trauma requiring admission to the SICU
• requirement for LMWH (Fragmin) therapy for prophylaxis of VTE as standard of care, and
• informed consent by patient, legally authorized representative or proxy decision maker (if patient incompetent to provide) obtained and documented.

Exclusion Criteria:

Presence of any of the following absolute contraindications to LMWH (Fragmin) therapy:

• known hypersensitivity to dalteparin sodium,
• known hypersensitivity to heparin or pork products,
• thrombocytopenia associated with positive tests for antiplatelet antibody in the presence of Fragmin,
• history of heparin-induced thrombocytopenia (HIT),
• chronic liver disease (bilirubin >2 mg/dl) or kidney insufficiency (CrCl <30mL/min),
• intravascular thrombolytic therapy within 24 hours,
• resuscitation that required massive transfusion (>10 units RBC within 6 hours),
• ongoing resuscitation for hemorrhagic shock,
• known bleeding disorder or coagulopathy (INR >2 not on warfarin),
• thrombocytopenia (platelets <20K/uL),
• subdural or epidural hematoma.

Or

Presence of any of the following relative contraindications to LMWH (Fragmin) therapy:

• new intracranial lesions, neoplasms or monitoring devices,
• extravascular thrombolytic therapy,
• severe uncontrolled hypertension,
• arterial dissection
• recent (within 12 hours) intraocular surgery (prior or planned),
• recent (within 72 hours) intracranial or spine surgery (prior or planned),
• conditions associated with increased risk of hemorrhage, e.g. active gastrointestinal ulceration, angiodysplastic disease, gastrointestinal bleeding within the past six months, bacterial endocarditis, history of hemorrhagic stroke, diabetic retinopathy.

Or

Presence, or removal within the last 12 hours, of an indwelling epidural or spinal catheter, OR recent (within the last 12 hours) or planned neuraxial (spinal/epidural) anesthesia or spinal puncture.

Or

Per history taken from patient or family, concomitant or known use within one week prior to hospitalization, of drugs affecting hemostasis such as NSAIDS, platelet inhibitors or other anticoagulants, except as specified in this protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Control (standard of care); Dalteparin sodium 5000IU subcutaneously daily	Drug: Dalteparin sodium; Dalteparin sodium injection 5000IU subcutaneously daily until fully ambulatory; Other Names: Dalteparin sodium (Fragmin)
EXPERIMENTAL: TEG-guided thromboprophylaxis; Dalteparin sodium plus/minus anti-platelet medication (aspirin) per a TEG-guided algorithm	Drug: Dalteparin sodium/aspirin; Dalteparin sodium (2500-10,000IU sc daily), aspirin (81-325mg daily) po.; Other Names: dalteparin sodium (Fragmin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypercoagulability	To determine the incidence of, and to characterize, hypercoagulability in a sample of trauma patients admitted to the SICU at DHMC using TEG and conventional clinical coagulation testing (APTT, INR), antithrombin III levels and protein C activity. Hypercoagulability is defined as TEG parameter G (clot strength) >10.9.	Study day five.
Incidence of VTE	The incidence and nature of hypercoagulability and the incidence of deep vein thrombosis and pulmonary embolism in each randomized group and in the subgroup receiving anti-platelet therapy in addition to Fragmin (descriptive analysis only)	Day 28 or discharge, whichever comes first.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TEG Parameters	R is a reaction time. The time from the start of a sample run until the first significant levels of detectable clot formation (amplitude = 2 mm in the TEG tracing). Rf is a difference in reaction time between Fragmin-active and Fragmin-neutralized samples. Achievement of a certain clot strength K is a measure of the time from R until a fixed level of clot strength is reached (amplitude = 20 mm). Angle or α measures the rapidity of fibrin build-up and cross-linking (clot strengthening). This most represents fibrinogen level. Angle relates to K, since both are a function of the rate of clot formation. MA, or Maximum Amplitude, is a direct function of the maximum clot strength. In tests where platelets are part of the clot, this parameter most reflects platelet function/aggregation. Clot strength is the result of two components - the modest contribution of fibrin and the much more significant contribution of the platelets.	Study day five.
International Normalized Ratio (INR)	Plasma based conventional coagulation testing parameters	Study day five.
Platelet Count	Platelet count measured by CBC test	Study day five.
TEG Parameters	Shear elastic modulus strength (SEMS). The MA parameter can be transformed into the actual measure of clot strength (G) using the formula below, and is measured in dyn/cm2 divided by 1000 (displayed in the software as Kd/sc). The absolute SEMS of the sample can be calculated from MA as follows: G = (5000MA/(100-MA))/1000 An amplitude of 50 mm corresponds to a SEMS of 5000 dyn/cm2. An increase in MA from 50 mm to 67 mm is equivalent to a two-fold increase in the SEMS. The G parameter not only provides a measurement of clot firmness in force units, but also is more indicative of small changes in the clot strength or clot breakdown than is the amplitude in mm because it is an exponential reflection of MA.	Study day five.
Conventional Coagulation Testing Parameters	Plasma based conventional coagulation testing parameters - Anti Xa	Study day five.
Conventional Coagulation Testing Parameters	Plasma based conventional coagulation testing parameters - Fibrinogen	Study day five.
Conventional Coagulation Testing Parameters	Plasma based conventional coagulation testing parameters - Anti-thrombin III	Study day five.
Conventional Coagulation Testing Parameters	Plasma based conventional coagulation testing parameters - Protein C	Study day five.

Collaborators and Investigators

• Sponsor: Denver Health and Hospital Authority
• Collaborators: Eisai Inc.
• Investigators: Principal Investigator: Ernest E. Moore Jr, M.D., Chief, Department of Surgery and Trauma Services , Denver Health Medical Center

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (ACTUAL): December 1, 2011
• Study Completion (ACTUAL): December 1, 2011

Study Registration Dates

• First Submitted: January 13, 2010
• First Submitted That Met QC Criteria: January 14, 2010
• First Posted (ESTIMATE): January 15, 2010

Study Record Updates

• Last Update Posted (ACTUAL): January 8, 2019
• Last Update Submitted That Met QC Criteria: December 15, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Prevention of venous thromboembolism
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Anticoagulants; Aspirin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: COMIRB # 09-0753