Eastern Diamondback Rattlesnake (Crotalus adamanteus) envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like enzyme (SVTLE) that is defibrinogenating, causing coagulopathy without effects on platelets in humans. This investigation utilized thrombelastographic methods to document this coagulopathy kinetically on the molecular level in a rabbit model of envenomation via the analyses of whole blood samples without and with platelet inhibition. Subsequently, the administration of a novel ruthenium compound containing site-directed antivenom abrogated the coagulopathic effects of envenomation in whole blood without platelet inhibition and significantly diminished loss of coagulation in platelet-inhibited samples. This investigation provides coagulation kinetic insights into the molecular interactions and results of SVTLE on fibrinogen-dependent coagulation and confirmation of the efficacy of a ruthenium antivenom. These results serve as a rationale to investigate the coagulopathic effects of other venoms with this model and assess the efficacy of this site-directed antivenom.

Background: Comatose survivors of out-of-hospital cardiac arrest (OHCA) undergoing percutaneous coronary intervention (PCI) and target temperature management (TTM) are at increased risk of stent thrombosis (ST), partly due to delayed platelet inhibition even with more potent P2Y12 agents. We hypothesized that periprocedural cangrelor would induce immediate platelet inhibition, bridging the \"P2Y12 inhibition gap\". Methods: In our pilot study, we randomized 30 comatose OHCA patients undergoing PCI and TTM (32-34 °C) into cangrelor and control groups. Both groups received unfractioned heparin, acetylsalicylic acid, and ticagrelor via enteral tube. The cangrelor group also received an intravenous bolus of cangrelor followed by a 4 h infusion. Platelet inhibition was measured using VerifyNow® and Multiplate® ADP at baseline and 1, 3, 5, and 8 h post PCI. Results: Patient characteristics did not differ between groups. VerifyNow® showed significantly decreased platelet reactivity with cangrelor at 1 h (30 vs. 221 PRU; p < 0.001) and 3 h (24 vs. 180 PRU; p < 0.001), with differences at 5 and 8 h. Similarly, the proportion of patients with high on-treatment platelet reactivity (HPR) in the cangrelor group was significantly lower at 1 h (0% vs. 67%; p < 0.001) and 3 h (0% vs. 47%; p = 0.007). Multiplate® ADP was also decreased at 1 h (14 vs. 48 U; p < 0.001) and 3 h (11 vs. 42 U; p = 0.001), with no difference at 5 and 8 h. The occurrence of bleeding events was similar in both groups. Conclusions: Cangrelor safely induced immediate and profound platelet inhibition. We observed no significant drug-drug interaction with ticagrelor.

UNASSIGNED: There are limited data to assess pharmacodynamic (PD) profiles of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and receiving cangrelor after pretreatment with ticagrelor.
UNASSIGNED: The PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is a prospective study conducted at Federico II University of Naples enrolling all patients undergoing PCI receiving cangrelor at operator\'s discretion. PD assessments were performed with 3 assays: (1) the gold standard light transmittance aggregometry (LTA) (20- and 5-μM adenosine diphosphate [ADP] stimuli); (2) VerifyNow P2Y12-test; (3) Multiplate electrode aggregometry (MEA), ADP-test.
UNASSIGNED: We analyzed 13 STEMI patients pretreated with ticagrelor within 1 h at the time they underwent primary PCI receiving cangrelor. All patients showed low maximal platelet aggregation at 30-minute during cangrelor infusion, as well as at 3 h and 4-6 h (corresponding to 1 h and 2-4 h after stopping cangrelor infusion) with no cases of high residual platelet reactivity. These results were consistent with all assays.
UNASSIGNED: PD data show that in contemporary real-world STEMI patients pretreated within 1 h with ticagrelor undergoing primary PCI, adding cangrelor resulted in fast and potent platelet inhibition, thus suggesting that cangrelor may bridge the gap until ticagrelor reaches its effect.

OBJECTIVE: Provision of pulmonary blood flow with a systemic-to-pulmonary artery shunt is essential in some patients with cyanotic congenital heart disease. Traditionally, aspirin (ASA) has been used to prevent thrombosis. We evaluated ASA dosing with 2 separate antiplatelet monitoring tests for accuracy and reliability.
METHODS: This is a retrospective, pre-post intervention single center study. Two cohorts were evaluated; the pre-intervention group used thromboelastography platelet mapping (TPM) and post-intervention used VerifyNow aspirin reactivity unit (ARU) monitoring. The primary endpoint was to compare therapeutic effect of TPM and ARU with regard to platelet inhibition. Inadequate platelet inhibition was defined as TPM <50% inhibition and ARU >550.
RESULTS: Data from 49 patients were analyzed: 25 in the TPM group and 24 in the ARU group. Baseline characteristics were similar amongst the cohorts. The TPM group had significantly more patients with inadequate platelet inhibition (14 [56%] vs 2 [8%]; p = 0.0006) and required escalation with additional thromboprophylaxis (15 [60%] vs 5 [21%]). There was no difference in shunt thrombosis (1 [2%] vs 0 [0%]; p = 0.32), cyanosis requiring early re-intervention (9 [36%] vs 14 [58%]; p = 0.11), or bleeding (15 [60%] vs 14 [58%]; p = 0.66).
CONCLUSIONS: With similar cohorts and the same ASA-dosing nomogram, ARU monitoring resulted in a reduced need for escalation of care and concomitant thromboprophylaxis with no difference in adverse outcomes. Our study suggests ARU monitoring compared with TPM may be a more reliable therapeutic platelet inhibition test for determining ASA sensitivity in children with congenital heart disease requiring systemic-to-pulmonary artery shunt.

BACKGROUND: A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs.
OBJECTIVE: PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results.
METHODS: Fifty-two privately owned CKCS with no or preclinical MMVD.
METHODS: Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography.
RESULTS: Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P < .0001) and Vel at 0.03 μM (P < .001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response.
CONCLUSIONS: The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.

BACKGROUND: Panax quinquefolius saponin (PQS) was shown beneficial against platelet adhesion and for gastroprotection. This study aimed to investigate the integrated efficacy of PQS with dual antiplatelet therapy (DAPT) on platelet aggregation, myocardial infarction (MI) expansion and gastric injury in a rat model of acute MI (AMI) and to explore the mechanism regarding arachidonic acid (AA)-derived eicosanoids metabolism.
METHODS: Wistar rats were subjected to left coronary artery occlusion to induce AMI model followed by treatment with DAPT, PQS or the combined therapy. Platelet aggregation was measured by light transmission aggregometry. Infarct size, myocardial histopathology was evaluated by TTC and H&E staining, respectively. Gastric mucosal injury was examined by scanning electron microscope (SEM). A comprehensive eicosanoids profile in plasma and gastric mucosa was characterized by liquid chromatography-mass spectrometer-based lipidomic analysis.
RESULTS: PQS+DAPT further decreased platelet aggregation, lessened infarction and attenuated cardiac injury compared with DAPT. Plasma lipidomic analysis revealed significantly increased synthesis of epoxyeicosatrienoic acid (EET) and prostaglandin (PG) I2 (potent inhibitors for platelet adhesion and aggregation) while markedly decreased thromboxane (TX) A2 (an agonist for platelet activation and thrombosis) by PQS+DAPT, relative to DAPT. DAPT induced overt gastric mucosal damage, which was attenuated by PQS co-administration. Mucosal gastroprotective PGs (PGE2, PGD2 and PGI2) were consistently increased after supplementation of PQS+DAPT.
CONCLUSIONS: Collectively, PQS+DAPT showed synergistic effect in platelet inhibition with ameliorated MI expansion partially through upregulation of AA/EET and AA/PGI2 synthesis while suppression of AA/TXA2 metabolism. PQS attenuated DAPT-induced gastric injury, which was mechanistically linked to increased mucosal PG production.

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The enhanced thrombotic milieu in diabetes contributes to increased risk of vascular events. Aspirin, a key antiplatelet agent, has inconsistent effects on outcomes in diabetes and the best dosing regimen remains unclear. This work investigated effects of aspirin dose and interaction with glycaemia on both the cellular and protein components of thrombosis.
A total of 48 participants with type 1 diabetes and 48 healthy controls were randomised to receive aspirin 75 or 300 mg once-daily (OD) in an open-label crossover study. Light transmittance aggregometry and fibrin clot studies were performed before and at the end of each treatment period.
Aspirin demonstrated reduced inhibition of collagen-induced platelet aggregation (PA) in participants with diabetes compared with controls, although the higher dose showed better efficacy. Higher aspirin dose facilitated clot lysis in controls but not individuals with diabetes. Collagen-induced PA correlated with glycaemic control, those in the top HbA1c tertile having a lesser inhibitory effect of aspirin. Threshold analysis suggested HbA1c levels of > 65 mmol/mol and > 70 mmol/mol were associated with poor aspirin response to 75 and 300 mg daily doses, respectively. Higher HbA1c was also associated with longer fibrin clot lysis time.
Patients with diabetes respond differently to the antiplatelet and profibrinolytic effects of aspirin compared with controls. In particular, those with elevated HbA1c have reduced inhibition of PA with aspirin. Our findings indicate that reducing glucose levels improves the anti-thrombotic action of aspirin in diabetes, which may have future clinical implications.
EudraCT, 2008-007875-26, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2008-007875-26 .

Background: Fast and adequate platelet inhibition is one of the cornerstones in the treatment of patients with ST-elevation myocardial infarction (STEMI). The aim of this analysis is to examine sex differences in platelet inhibition in the acute treatment of STEMI patients. Methods: Platelet reactivity units (PRU) and ticagrelor plasma concentrations of all patients in the ON-TIME 3 were compared according to sex. All patients were pre-treated with crushed ticagrelor, aspirin and heparin. Both univariable and multivariable analyses were performed. Results: In this sub-analysis of the ON-TIME 3 trial, 195 STEMI patients, of which 58 female patients (29.7%) and 137 male patients (70.3%), were analyzed. PRU-values immediately post-PCI were not different in females [median 135 (IQR 47-228)] compared to males [160 (IQR 40-219), P = 0.92]. Ticagrelor plasma concentrations were higher in the females at the start of primary PCI [141 ng/mL (IQR 25-491) vs. 76 ng/mL (IQR 15-245), P = 0.049] and at 6 hours post-primary PCI [495 ng/mL (IQR 283-661) vs. 321 ng/mL (IQR 196-537), P = 0.001] compared to males. However, immediately post-primary PCI and at 1-hour post-primary PCI no significant differences in ticagrelor concentrations were seen between sexes. In multivariable analysis, sex was significantly associated with ticagrelor concentration (P = 0.04), but not with PRU (P = 0.93). Conclusion: Effective platelet inhibition reached by crushed ticagrelor in STEMI patients was similar in both sexes. Females had similar or even higher ticagrelor plasma concentrations up to 6 hours post-primary PCI compared with males.

Antiplatelet medications are the mainstay for secondary stroke treatment. Aspirin, clopidogrel, and aspirin-dipyridamole are commonly used antiplatelet medications. Other antiplatelet medications such as ticagrelor and prasugrel have been majorly used in cardiovascular or neuro-interventional specialties. Recent studies have paved a way to their use in secondary stroke prevention. In this review, we have briefly discussed the pharmacology of ticagrelor, published literature in cardiology and stroke trials, use of ticagrelor among patients with ischemic strokes, and compared its efficacy, limitations and side-effects with other antiplatelet medications.