Stent thrombosis mechanism and pathophysiology

Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview
Stent thrombosis (ST) occurs due to variety of factors inducing thombogenesis. Being an invasive procedure, the trauma from coronary stenting can itself cause platelet activation and thombogenic cascade. There is either creation or an enhancement of a thrombogenic milieu by:


 * creating an environment conducive for platelet activation and/or
 * creating an environment conducive for in-stent thrombosis

These processes are facilitated by


 * Creating a thrombogenic milieu by
 * Slow coronary flow,
 * local dissection,
 * distal untreated critical lesion
 * poor out flow


 * Persistence of, or creation of substrate for platelet activation
 * Exposure of platelet activating factors due to trauma of stenting or ballooning – acutely
 * Persistant incomplete endotheliazation
 * Inadequate platelet inhibition – due to inadequate dosing or drug unresponsiveness.
 * acutely
 * subacutely
 * long term


 * Dosing issues
 * with anti thrombotic medications (acutely)
 * antiplatelet medications (acutely, sub-acutely or long term)
 * inadequate time for the loading dose to act
 * suboptimal/sub-therapeutic dosing during the procedure or thereafter


 * Resistance to antiplatelet medications
 * Aspirin resistance
 * Clopidogrel resistance


 * Deranged homeostasis due to disease creating a prothrombotic diathesis
 * sepsis
 * blood transfusions
 * surgery (In one study, following BMS, mortality rate among patients who had non cardiac surgery within two-weeks was 32%, almost exclusively due to ST).
 * dehydration
 * Other states which may create hypotensive states. (eg. of anecdotal reports of stent thrombosis with defecation syncope)

Mechanisms and pathophysiology of ST
ST in Bare Metal Stent (BMS):

After BMS implantation, near-complete endothelization has been shown to occur by 3 to 4 months.

This coincides with the reduction of risk of ST.

ST in Drug Eluting Stent (DES):

Factors that serve as nidus for development stent thrombosis are:
 * Delayed endothelialization.


 * Inflammatory response to the stent material.


 * Hypersensitivity reaction around the stent material in DES serving as nidus for ST.


 * Antineoplastic therapy and delayed endothelialization had been an issue with late ST seen with brachytherapy.
 * Coronary brachytherapy use has all but disappeared since the introduction of DES.

Clinical Trial Data

 * An angioscopic study of stented coronary segments showed that neointimal coverage was complete only in 2 out of 15 patients with sirolimus stents and all of 22 BMS at three to six months. There were thrombi in most of the stented segments which were not seen on angiography which were more common with incomplete neointimal coverage.  In a study involving serial angioscopy after sirolimus-eluting stent (SES) implantation at 4, 11, and 21.2 ±2.2 months showed that neointimal coverage after sirolimus-eluting stent implantation was incomplete even at that late stage.


 * In a post mortem analysis, DES, compared to BMS had delayed endothelial healing. This group was more likely to have ST.


 * A post mortem analysis of a patient dying from an unrelated cause but who also had a DES implanted, revealed poor endothelial cell junction formation and micro-thrombi of focal platelet aggregation at 16 months after rapamycin stent implantation.


 * Evidence of an inflammatory response was present in nearly 9% of the sirolimus eluting stents (SES) and paclitaxel eluting stents (PES) by the demonstration of late aquired stent malaposition (LASMA) which was more than what was seen with BMS.


 * Cypher and Taxus DES were shown to provoke chronic eosinophilic infiltration and inflammation of the arterial wall potentially predisposing patients for thrombosis


 * Both red and white thrombi have been demonstrated within sirolimus eluting stents (SES) as a cause of late stent thrombosis