Thrombin‐Induced Platelet‐Fibrin Clot Strength Identified by Thrombelastography

Bliden, Kevin P.; Tantry, Udaya S.; Gesheff, Martin G.; Franzese, Christopher; Pandya, Shachi; Tóth, Peter P.; Mathew, Denny; Chaudhary, Rahul; Gurbel, Paul A.

doi:10.1111/joic.12277

Cited by 15 publications

(6 citation statements)

References 47 publications

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“…preexisting hypercoagulable state. As noted by our group in a prior study, TIP-FCS >67 mm is associated with a thrombotic phenotype predictive of restenosis, which was observed in the case discussed [7]. An alternate explanation of the observed hypercoagulability could be from the high number of stents implanted as opposed to intrinsic patient-related factors.…”

supporting

confidence: 69%

21 Re-Stenosed Stents in the Presence of Adequate P2Y12 Inhibition: A Case Report

Padilha

Chaudhary

Rout

et al. 2019

BJSTR

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In-stent restenosis (ISR) is an important complication observed after stent implantation with percutaneous coronary intervention (PCI) and is clinically defined as the onset of recurrent angina symptoms or objective evidence of myocardial ischemia.Angiographically, it is defined by ≥50% luminal diameter stenosis in the stented segment. The incidence of ISR varies with the type of stent used, patient and lesion characteristics, and procedural factors. The patient-related factors associated with late ISR (>30 days) include poor response to antiplatelet drugs, diabetes, malignancy, renal failure, and acute coronary syndrome (ACS) at presentation [1]. Higher rates of ISR are seen with increasing complexity of lesions. Data from meta-analysis and registries show a similar rate of early (<30 days) and late (>30 days but less than 1 year) ISR between bare-metal stents (BMS) and first-generation drug eluting stents (DES) [2,3]. With introduction of second-generation DES, rates of ISR have been reduced to 1.5% -2.3% at 1 year [4,5]. The underlying pathophysiology of DES-ISR involves a complex interplay between platelets, leukocytes, coagulationfibrinolysis system, various growth factors and pro-inflammatory cytokines. We present a case of a patient who underwent ISR in 21 stents despite being on adequate P2Y12 inhibition. This case highlights the role of coagulation pathways other than platelets in pathogenesis of ISR. Case Presentation 67-year-old Caucasian woman with past medical history of diabetes type 2, hypertension, peripheral vascular disease and severe coronary artery disease status post coronary artery bypass grafting 12 years ago (saphenous vein graft [SVG] to the first and third marginal branches of left circumflex artery, SVG to

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supporting

confidence: 69%

21 Re-Stenosed Stents in the Presence of Adequate P2Y12 Inhibition: A Case Report

Padilha

Chaudhary

Rout

et al. 2019

BJSTR

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“…Moreover, pharmacodynamic studies have ignored potential effects of vorapaxar on the viscoelastic and kinetic characteristics of platelet-fibrin clot formation, potential factors that may play a role in the development of adverse thrombotic events 18. In the Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets study (CLEAR Platelets II study), Gurbel et al 19 demonstrated a significant reduction in thrombin-induced platelet-fibrin clot strength with GPIIb/IIIa blockade with eptifibatide and a non-significant reduction using a direct thrombin inhibitor bivalirudin in patients undergoing elective coronary stenting.…”

mentioning

confidence: 99%

Effects of vorapaxar on clot characteristics, coagulation, inflammation, and platelet and endothelial function in patients treated with mono‐ and dual‐antiplatelet therapy

Bliden¹,

Chaudhary

Kuliopulos

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Vorapaxar is indicated with standard antiplatelet therapy (APT) in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). Objectives: To evaluate the comparative effects of vorapaxar on platelet-fibrin clot characteristics (PFCC), coagulation, inflammation, and platelet and endothelial function during treatment with daily 81 mg aspirin (A), 75 mg clopidogrel (C), both (C + A), or neither. Methods: Thrombelastography, conventional platelet aggregation (PA), ex vivo endothelial function by ENDOPAT, coagulation, platelet activation/inflammation marked by urinary 11-dehydrothromboxane B 2 (UTxB 2 ) and safety were determined in patients who were APT naïve (n = 21), on C (n = 8), on A (n = 29), and on A + C (n = 23) during 1 month of vorapaxar therapy and 1 month of offset. Results: Vorapaxar had no effect on PFCC, ADP-or collagen-induced PA, thrombin time, fibrinogen, PT, PTT, von Willebrand factor (vWF), D-dimer, or endothelial function (P > .05 in all groups). Inhibition of SFLLRN (PAR-1 activating peptide)-stimulated PA by vorapaxar was accelerated by A + C at 2 hours (P < .05 versus other groups) with nearly complete inhibition by 30 days that persisted through 30 days after discontinuation in all groups (P < .001). SFLLRN-induced PA during offset was lower in APT patients versus APT-naïve patients (P < .05). Inhibition of UTxB 2 was observed in APT-naive patients treated with vorapaxar (P < .05). Minor bleeding was only observed in C-treated patients. Conclusion: Vorapaxar had no influence on PFCC measured by thrombelastography, coagulation, or endothelial function irrespective of APT. Inhibition of protease activated receptor (PAR)-1 mediated platelet aggregation by vorapaxar was accelerated by A + C and offset was prolonged by concomitant APT. Vorapaxar-induced anti-inflammatory effects were observed in non-aspirin-treated patients.

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“…Considering the rapidly increasing number of cardiovascular patients 4 , restenosis has become a significant clinical concern. There are many pathological features of in-stent restenosis that limit the efficacy of percutaneous intervention 5 , including dysfunctional endothelial cells, proliferation and migration of vascular smooth muscle cells (VSMCs), and activation of inflammation 6 . As the principal component of vascular walls, VSMCs play crucial roles in both the physiological functions of blood vessels and the formation atherosclerotic lesions 7 .…”

mentioning

confidence: 99%

The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-β1 pathway

Tang

Pei

Yang

et al. 2016

Sci Rep

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Restenosis limits the efficacy of vascular percutaneous intervention, in which vascular smooth muscle cell (VSMC) proliferation and activation of inflammation are two primary causal factors. Calpains influence VSMC proliferation and collagen synthesis. However, the roles of calpastatin and calpains in vascular restenosis remain unclear. Here, restenosis was induced by ligating the left carotid artery, and VSMCs were pretreated with platelet-derived growth factor (PDGF)-BB. Adenovirus vector carrying MMP2 sequence and specific small interfering RNA against calpain-1/2 were introduced. Finally, restenosis enhanced the expression of calpain-1/2, but reduced calpastatin content. In calpastatin transgenic mice, lumen narrowing was attenuated gradually and peaked on days 14–21. Cell proliferation and migration as well as collagen synthesis were inhibited in transgenic mice, and expression of calpain-1/2 and MMP2/transforming growth factor-β1 (TGF-β1). Consistently, in VSMCs pretreated with PDGF-BB, calpastatin induction and calpains inhibition suppressed the proliferation and migration of VSMCs and collagen synthesis, and reduced expression of calpain-1/2 and MMP2/TGF-β1. Moreover, simvastatin improved restenosis indicators by suppressing the HIF-1α/calpains/MMP2/TGF-β1 pathway. However, MMP2 supplementation eliminated the vascular protection of calpastatin induction and simvastatin. Collectively, calpains inhibition plays crucial roles in vascular restenosis by preventing neointimal hyperplasia at the early stage via suppression of the MMP2/TGF-β1 pathway.

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Thrombin‐Induced Platelet‐Fibrin Clot Strength Identified by Thrombelastography

Abstract: Patients with ISR identified at the time of cardiac catheterization have a prothrombotic phenotype indicated by high TIP-FCS, a novel marker. Studies to confirm the prognostic utility of high TIP-FCS for the development of ISR are ongoing.

Cited by 15 publications

References 47 publications

21 Re-Stenosed Stents in the Presence of Adequate P2Y12 Inhibition: A Case Report

21 Re-Stenosed Stents in the Presence of Adequate P2Y12 Inhibition: A Case Report

Effects of vorapaxar on clot characteristics, coagulation, inflammation, and platelet and endothelial function in patients treated with mono‐ and dual‐antiplatelet therapy

The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-β1 pathway

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