Thromboelastography With Platelet Mapping to Guide Antiplatelet Therapy After Lower Extremity Revascularization

The Use of Thromboelastography With Platelet Mapping to Guide Thromboprophylaxis Following Lower Extremity Revascularization for Peripheral Artery Disease

The goal of this clinical trial is to learn if a blood clotting test called thromboelastography with platelet mapping (TEG-PM) can guide blood-thinning medication decisions in adults 18 years and older with peripheral artery disease (PAD) who have undergone leg artery open or endovascular surgery. The main questions it aims to answer are:

• Can TEG-PM results improve blood-thinning medication levels in participants at high risk for blood clots after surgery?
• Can adjusting blood-thinning medications based on TEG-PM results lower the rate of blood clots forming in their revascularized leg after surgery?

Participants will:

• Have blood samples taken before surgery and at 1 week, 1 month, 2 months, 3 months, 6 months, and up to 9 months after surgery
• Have blood-thinning medications (aspirin, clopidogrel, and/or ticagrelor) adjusted based on TEG-PM results during the first 3 months after surgery
• Have one additional blood test to check if clopidogrel is working properly
• Have their medical records reviewed for 6 months after their last visit to check on their health outcomes

Background and Scientific Rationale:

Peripheral artery disease (PAD) frequently requires lower extremity revascularization via bypass surgery or endovascular stenting. Despite standard antiplatelet therapy, thrombosis occurs in up to 17% of patients within 6 months of revascularization. Current thromboprophylaxis strategies apply a uniform approach that fails to account for substantial interpatient variability in platelet response, including the fact that 60-65% of patients exhibit partial or complete resistance to aspirin or clopidogrel.

Thromboelastography with platelet mapping (TEG-PM) is a viscoelastic point-of-care test that provides a comprehensive assessment of the coagulation cascade, including clot initiation, kinetics, strength, fibrinolysis, and platelet function. TEG-PM measures adenosine diphosphate (ADP)-mediated platelet inhibition, reflecting P2Y12 pathway activity and clopidogrel effect, and arachidonic acid (AA)-mediated platelet inhibition, reflecting cyclooxygenase pathway activity and aspirin effect.

Prior prospective observational work by this group in 82 patients demonstrated that TEG-PM can identify individualized mechanisms of hypercoagulability prior to thrombotic events, providing a clinically actionable window for intervention. Patients who experienced thrombotic events showed significantly lower platelet inhibition and higher platelet aggregation than those who did not thrombose. Preliminary analysis identified platelet aggregation greater than 70.8% and platelet inhibition below 27.5% as associated with thrombosis with 85% sensitivity. The optimal cutoff for ADP maximum amplitude (MA) indicating higher thrombosis risk was greater than 42mm with 82% sensitivity.

TEG-Guided Antiplatelet Protocol:

This study implements a step-up approach to antiplatelet therapy guided by serial TEG-PM results using the following prespecified thresholds:

• Platelet inhibition not greater than 30% AND platelet aggregation not less than 70% = high risk → therapy escalation
• ADP MA not less than 42mm = high risk → therapy escalation
• Values within therapeutic range → continue current regimen

Escalation follows this stepwise sequence:

1. Aspirin monotherapy (81 mg daily)
2. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel (75 mg daily)
3. DAPT with aspirin and ticagrelor (90 mg twice daily) replacing clopidogrel
4. Triple antiplatelet therapy (aspirin, clopidogrel, and ticagrelor) if platelet activity goals still not met

Participants with persistent high-risk TEG profiles despite ticagrelor are referred for genetic testing.

TEG-PM Blood Sampling and Analysis:

Two sample types are collected at each visit:

• Citrated blood (sodium citrate Vacutainer tubes): incubated at room temperature for 10 minutes; analyzed using citrated multichannel cartridges to assess coagulation initiation, kinetics, clot strength, and fibrinolysis. Must be processed within 2-4 hours of collection.
• Heparinized blood (sodium heparin Vacutainer tubes): incubated at room temperature for 30 minutes; analyzed using PlateletMapping cartridges to measure ADP-mediated and AA-mediated platelet aggregation and inhibition. - Must be processed within 2 hours of collection.

All samples are analyzed using the TEG 6s Hemostasis Analyzer (Haemonetics Corporation, Boston, MA) per manufacturer specifications. Up to two citrated tubes and one heparinized tube are drawn at each timepoint. In the event of insufficient blood volume, TEG-PM will be prioritized.

Study Phases:

1. Pre-operative Phase:

   Blood sample collected within 48 hours before the planned revascularization procedure. If the procedure is delayed or rescheduled beyond this window, a new sample is collected.

2. Interventional Phase (1 Week through Month 3):

TEG-PM results guide antiplatelet medication adjustments at the following visits:

• 1 week (7-26 days post-procedure)
• 1 month (27-54 days)
• 2 months (55-84 days)
• 3 months (85-149 days)

Unscheduled visits may occur if the principal investigator deems additional sampling necessary for patient safety, including readmission, clotting event, bleeding event, reintervention, inconclusive results, or medication change after 7 days.

Observational Phase (Month 6 through Month 9):

TEG-PM samples are collected at standard of care appointments. No medication adjustments are made during this phase:

• 6 months (150-220 days)
• 9 months (240-360 days): applicable only to participants still taking ticagrelor at the Month 6 visit

Medical Record Review:

Participants are followed for 6 additional months after their last sample collection visit via medical record review only to assess clinical outcomes.

Medication Adherence Criteria:

TEG-PM results are used to guide therapy only when participants are confirmed adherent:

• Antiplatelet therapy: most recent dose taken within 7 days of sampling
• Anticoagulant therapy: most recent dose taken within 72 hours of sampling

Clopidogrel Resistance Testing:

All participants undergo one-time clopidogrel resistance testing using the VerifyNow P2Y12 assay, an FDA-approved point-of-care test. Testing is performed at any post-operative study visit after the participant has been taking clopidogrel for at least 7 days. One citrated blood tube (3cc) is collected at MGH and couriered to Brigham and Women's Hospital hematology laboratory for analysis.

Disease Severity Assessment:

Peripheral artery disease severity is assessed at each study visit using the Rutherford Chronic Limb Ischemia Classification System based on standardized scripted questions addressing:

• Walking frequency and distance before pain onset
• Presence of rest pain or nocturnal pain
• Presence of non-healing wounds

Inclusion Criteria:

• Patients requiring infrainguinal endovascular revascularization for peripheral atherosclerosis
• Patients of age 60 or older

Exclusion Criteria:

• Planned open surgical revascularization (bypass grafting, endarterectomy)
• Hybrid procedures involving a significant open surgical component
• Contraindication to standard antiplatelet therapy
• Pregnancy or breastfeeding
• Inability to undergo serial venous blood sampling
• Inability to provide informed consent
• Technical failure to cross or treat the target lesion via an endovascular approach
• Non-atherosclerotic pathology identified as primary etiology