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

Background and Scientific Rationale

Peripheral artery disease (PAD) affects more than 200 million people worldwide and frequently requires lower extremity revascularization, most commonly by endovascular approaches. Despite guideline-directed antiplatelet therapy, thrombotic occlusion or clinically significant restenosis occurs in approximately 20% of patients within 12 months of revascularization and is a leading cause of repeat intervention and amputation. Current thromboprophylaxis strategies apply a uniform regimen that does not account for substantial interpatient variability in platelet response; 60-65% of vascular patients exhibit partial or complete resistance to aspirin or clopidogrel.

Thromboelastography with platelet mapping (TEG-PM) is a point-of-care whole-blood viscoelastic assay that assesses clot initiation, kinetics, strength, and fibrinolysis, as well as pathway-specific platelet function. These include adenosine diphosphate (ADP)-mediated platelet inhibition, which reflects P2Y12 pathway activity and clopidogrel/ticagrelor effect, and arachidonic acid (AA)-mediated platelet inhibition, which reflects cyclooxygenase pathway activity and aspirin effect.

In prior prospective observational work, this group demonstrated that an ADP-mediated platelet inhibition value below 29.2% predicted thrombosis or clinically significant stenosis after lower extremity revascularization with 87% sensitivity and 70% specificity (Majumdar et al., J Am Heart Assoc 2023). Subsequent work identified high ADP-mediated platelet inhibition as associated with bleeding risk (Rodriguez Alvarez et al., J Surg Res 2025). A pilot study implementing TEG-PM-guided therapy was associated with reduced thrombosis or clinically significant stenosis compared with historical institutional rates (Suarez et al., Ann Surg 2024). Based on these findings, the Thromboprophylaxis for Arterial Revascularization to Guide Elderly Therapy (TARGET) protocol was developed.

TARGET Protocol (TEG-PM-Guided Antiplatelet Therapy)

Postoperative antiplatelet therapy is adjusted according to ADP-mediated platelet inhibition on TEG-PM:

Platelet inhibition <30% (hypercoagulable; increased thrombosis/stenosis risk) → escalate antiplatelet therapy.

Platelet inhibition 30-86% (therapeutic range) → continue current regimen. Platelet inhibition >86% (hypocoagulable; increased bleeding risk) → de-escalate antiplatelet therapy.

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 hypercoagulability persists

De-escalation follows the same sequence in reverse order. Participants whose platelet inhibition values fall outside protocol-defined ranges or remain abnormal despite adjustment are referred to hematology for further evaluation.

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 (through 6 months):

TEG-PM samples are collected at 1, 3, and 6 months after the index procedure, and the results guide antiplatelet adjustments per the TARGET protocol.)

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.

Follow-up phase (6-12 months):

After the 6-month visit, antiplatelet management is transferred to the treating surgeon. Clinical follow-up continues through 12 months, at visits approximately 1, 3, 6, and 12 months after the procedure.

Outcome ascertainment:

Outcomes are determined from clinic visits, hospitalizations, procedural reports, imaging, and medical record review through 12 months. For participants who discontinue study visits, ascertainment continues through medical record review.

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:

Participants taking clopidogrel undergo one-time clopidogrel resistance testing using the VerifyNow P2Y12 assay after at least 7 days of therapy. One citrated blood tube (3cc) is collected at MGH and couriered to Brigham and Women's Hospital hematology laboratory for analysis.

Disease Severity Assessment:

PAD severity is assessed using Rutherford clinical category, index-limb ankle-brachial index, and toe-brachial index. Rutherford category 4 defines ischemic rest pain and categories 5-6 define ischemic tissue loss.

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

Outcomes and Comparator

The main clinical endpoint is a composite of thrombosis or clinically significant stenosis of the treated arterial segment within 12 months. Clinically significant stenosis is defined as duplex PSV >300 cm/s and PSVR ≥3.5, accompanied by recurrent ischemic symptoms, an ABI decrease >0.2 from post-procedure, or repeat target-lesion revascularization. Secondary endpoints include major amputation of the index limb, amputation-free survival, all-cause mortality, ISTH major bleeding, and ISTH clinically relevant non-major bleeding.

Outcomes are compared with a prospectively collected historical observational cohort enrolled at the same institution from December 2020 to December 2022 (IRB protocol 2022P001918). That cohort met the same eligibility criteria and underwent serial TEG-PM testing, but the results were blinded to treating clinicians, and antiplatelet therapy followed standard of care.

A minimum of 107 TARGET participants was required to provide 80% power at two-sided α = 0.05, based on effect sizes from the pilot study.