P2Y12 receptor inhibitors for secondary prevention of ischemic stroke

Introduction: Ischemic stroke (IS) is a major cause of death and disability worldwide. The P2Y₁₂ receptor plays a critical role in the formation of a stable thrombus leading to ischemic complications. Therefore, P2Y₁₂ receptor inhibitors constitute a major antiplatelet strategy in the secondary prevention of IS.

Areas covered: We searched articles about P2Y₁₂ receptor inhibitors and stroke in PubMed published until December 2014. This is a comprehensive review of the role of P2Y₁₂ receptor inhibitors alone and in combination with aspirin in the secondary prevention of noncardioembolic stroke.

Expert opinion: The potential benefit of more potent antiplatelet therapy for secondary stroke prevention must be weighed against the risk of bleeding in patients with IS. Short-term (≤ 3 months) dual antiplatelet therapy with clopidogrel and aspirin that is initiated early after IS or transient ischemic attack due to large artery atherosclerosis appears most efficient.     

Congenital and acquired ADAMTS13 deficiency: Two mechanisms,one patient

Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening microangiopathy with a heterogeneous and largely unpredictable course. It is caused by ADAMTS13 deficiency, that can be either congenital or due to anti‐ADAMTS13 autoantibodies development. ADAMTS13 deficiency is necessary but not always sufficient to cause acute clinical manifestations and trigger factors may be needed. We report the case of a woman diagnosed with congenital TTP in her adulthood, presenting with anti‐ADAMTS13 autoantibodies in acute phase during ticlopidine consumption. Noteworthy, the two ADAMTS13 mutations identified in this patient are novel: one is a splice‐site mutation located in intron 11 (c.1308+2_5delTAGG) and the other is a point missense mutation in exon 29 (c.4184T>C leading to p.Leu1395Pro substitution). Since congenital TTP is an extremely rare disease and drug‐induced TTP is an uncommon side effect of treatment with ticlopidine, the simultaneous occurrence of both mechanisms of disease in one patient is exceptional. This case represents TTP as a multifactorial disease, with ADAMTS13 genetic abnormality and environmental exposures acting together in determining individual clinical phenotype. J. Clin. Apheresis 30:252–256, 2015. © 2014 Wiley Periodicals, Inc.     

Ticlopidine-induced aplastic anemia: two new case reports,review, and meta-analysis of 55 additional cases

Ticlopidine-induced aplastic anemia (TIAA) is considered very uncommon. We present two new cases, and we review 55 additional cases from the literature. The first case concerns a 70-year-old man who developed severe aplastic anemia 7 weeks after treatment with 500 mg of ticlopidine daily. The patient sustained a severe septic episode, was treated with antibiotics and GM-CSF, and recovered the 14(th) day after ticlopidine withdrawal. The second was an 82-year-old man receiving ticlopidine for 2 years when, during a febrile episode, he was found neutropenic with marrow aplasia. Ticlopidine withdrawal and treatment with antibiotics, transfusions, and G-CSF helped him to recover. When the data of the 57 patients are evaluated, a reversible direct cytotoxic effect of ticlopidine on the pluripotent/bipotent hematopoietic progenitor stem cell is proposed. It is estimated that the real incidence if TIAA is higher, and many cases, initially presented as agranulocytosis +/- thrombocytopenia, might be true aplastic anemias, not proven by marrow aspiration or trephine biopsy. There is no effective monitoring to prevent this side effect. Recombinant growth factors appear not to help in shortening the neutropenic period.     

Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation

BACKGROUND: Monocyte activation induces different procoagulant and proadhesiveinflammatory responses and thus may play a role in thromboticcomplications after coronary interventions. Monocyte-plateletinteraction may trigger these effects inducing monocyte activation. AIMS: To characterize the effect of antiplatelet vs anticoagulationtherapy on monocyte-platelet interaction and monocyte functionafter intracoronary stenting. METHODS AND RESULTS: Immediately before, and during the first 12 days after successfulcoronary stenting, monocyteplatelet conjugates and monocytefunction were assessed by flow cytometric detection of GPIIb/IIIa(CD41) on monocytes and by monocyte surface exposure of Mac-1(CD11b/ CD18) and L-selectin (CD62L). Twenty patients receivingcombined antiplatelet therapy (ticlopidine, aspirin) were comparedto 20 patients with standard anticoagulation (phenprocoumon,overlapping heparin, aspirin). Before stenting, monocyte-plateletconjugates and Mac-1 surface expression in both groups weresignificantly increased, while L-selectin was significantlydiminished. Anticoagulation did not change these variables significantlyduring the subsequent 12 days. In contrast, antiplatelet therapyreduced platelet-monocyte conjugates by 46±9·3%(mean±SEM, P=0·0019) within 4 days, which wasassociated with a decrease in Mac-1 expression (28±6·7%,P=0·0013) and an increase in L-selectin (56±15·0%,P=0·0061). CONCLUSION: After intracoronary stenting, combined antiplatelet therapy,but not anticoagulation, causes reduction of monocyte-plateletinteraction, which is associated with monocyte deactivation.This may contribute to a decreased risk for thrombotic events.     

Ticlopidine Enhances the Platelet Inhibitory Capacity of Abciximab In Vitro

Ticlopidine and abciximab are two antiplatelet agents that are frequently administered during percutaneous coronary interventions. Although they have different mechanisms of action and pharmacological profiles, the two agents are often concomitantly used in complicated stent placements. The purpose of the study was to evaluate the effect of ticlopidine therapy on the capacity of abciximab to inhibit platelet aggregation, in vitro. Blood samples from 13 ticlopidine-treated stent placement patients and 8 patients undergoing PTCA who did not receive ticlopidine were obtained prior to, 12–36 hours and 7–10 days after initiating ticlopidine treatment. For each patient, the minimal ADP and the thrombin receptor activating peptide (TRAP) concentrations that elicited maximal platelet aggregation responses at baseline were used to measure the extent of platelet aggregation and the abciximab concentration that gave a 50% decrease in aggregation (IC₅₀) for both agonists at the three time points. The ticlopidine group baseline and 12–36 hour mean ADP aggregation responses were equivalent, but decreased by 34% (P = 0.009) at 7–10 days. The control group ADP and TRAP, as well as the ticlopidine group TRAP aggregation responses, were equivalent at all time points. The ticlopidine group baseline and 12–36 hour abciximab IC₅₀ values for ADP were comparable (1.58 ± 1.1 ng/mL vs. 1.23 ± 0.5 ng/mL; P = 0.266), but decreased to 1.00 ± 0.6 ng/mL (36%; P = 0.004) at 7–10 days. In contrast, the abciximab IC₅₀ for TRAP increased from 1.48 ± 1.0 ng/mL to 1.85 ± 1.1 ng/mL (25%; P = 0.033) at 12–36 hours, but returned to baseline at 7–10 days (1.40 ± 0.8; P = 0.975). The control group IC₅₀ abciximab values for ADP and TRAP were comparable throughout the monitoring period. The results demonstrate that ticlopidine elicits subtle potentiation of the platelet-inhibitory capacity of abciximab to the agonist ADP, but not TRAP, at 1 week after initiation of treatment.     

Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection

Summary.  The definition 'resistance to antiplatelet drugs' should be limited to situations in which failure of the drug to hit its pharmacological target has been documented by specific laboratory tests. Aspirin resistance, as determined by specific tests (e.g. serum thromboxane B₂), appears to be rare (1–2%) and, in most instances, is caused by poor compliance. In contrast to aspirin, studies that used specific tests to measure the pharmacological effect of thienopyridines [e.g. vasodilator-stimulated phosphoprotein (VASP)] showed a wide variability of responses to these drugs, with significant proportions of subjects (15–30%) who are very poor responders. Inter-individual differences in the extent of metabolism of thienopyridines to their active metabolites is the most plausible mechanism for the observed inter-individual variability in platelet inhibition. The demonstration that some patients may be 'resistant' or 'poor responders' to the pharmacological effect of antiplatelet drugs, has prompted the need of laboratory monitoring of antiplatelet therapy. However, many published studies have been performed using unspecific tests of platelet function, which identify patients on antiplatelet treatment with high residual platelet reactivity, which is not necessarily because of resistance to antiplatelet drugs. Despite this drawback, identification of patients with high residual platelet reactivity may be useful to predict their risk of atherothrombotic events. However, many studies still need to be carried out to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring antiplatelet therapy can be recommended in the clinical practise. Until then, monitoring of antiplatelet therapy should be considered for investigational purposes only.     

噻氯匹啶抑制EDTA依赖性血小板聚集在临床中的应用

目的　探讨噻氯匹啶在体外对 EDTA依赖性血小板聚集的抑制作用。方法　采用 COULTERSTKS血细胞分析仪分析噻氯匹啶在体外对 EDTA聚集者血小板计数的影响。结果　加入噻氯匹啶后在2 h内其血小板计数与 EDTA抗凝时测的结果有显著差异 ( P<0 .0 1 ) ,而与手工计数无显著性差异 ( P>0 .0 5 ) ,同时 MPV测定也无显著性差异 ( P>0 .0 5 )。结论　噻氯匹啶是一种较强的抗血小板活化药物 ,对EDTA依赖性血小板聚集有很好的抑制作用 ,适用于临床血小板的测定。     

Comparison of beraprost and ticlopidine in Chinese patients with chronic peripheral arterial occlusion: a multicenter, single-blind, randomized, controlled study

Background: Chronic peripheral arterial occlusion (CPAO) is a progressive disease that is associated with a variety of symptoms, the 4 most common being a sensation of coolness in the limbs, intermittent claudication (in which pain occurs on walking), limb pain (which occurs spontaneously at rest), and ischemic leg ulcers. Beraprost sodium is an oral prostaglandin I₂ analogue that may ameliorate these symptoms.Objective: The aim of this study was to compare the efficacy and tolerability of beraprost sodium and ticlopidine hydrochloride in the treatment of patients with CPAO in China.Methods: In this multicenter, single-blind, controlled study, patients with CPAO were randomly assigned to receive beraprost 120-μg tablet TID or ticlopidine 500-mg tablet BID, both administered orally. The clinical efficacy of the drugs was assessed using the 4 main symptoms of CPAO. Ankle-brachial index (ABI) also was measured as a clinical pharmacologic procedure. Adverse events were assessed throughout the study.Results: A total of 124 patients (96 men, 28 women; mean [SD] age, 65 [12] years) were enrolled in 3 hospitals. Data from 119 patients (93 men, 26 women; mean [SD] age, 65 [12] years) were included in the efficacy analysis (64 and 55 patients in the beraprost and ticlopidine groups, respectively). Although all 4 symptoms of CPAO were ameliorated after 3 and 6 weeks of treatment with both drugs, only the cool sensation was significantly improved with beraprost compared with ticlopidine at 6 weeks (P<0.05). ABI was significantly increased with both beraprost and ticlopidine at 6 weeks versus baseline (P<0.001 and P<0.01, respectively), suggesting that this pharmacologic action may have led to their beneficial effect on various symptoms. The tolerability analysis included 123 patients (65 and 58 patients in the beraprost and ticlopidine groups, respectively). The numbers of patients who (1) experienced adverse events (AEs), (2) experienced adverse drug reactions, and (3) withdrew due to AEs were significantly smaller in the beraprost group than in the ticlopidine group (P<0.001, P<0.05, and P<0.05, respectively).Conclusions: In this study population of patients with CPAO, beraprost ameliorated cool sensation in the limbs, intermittent claudication, limb pain, and ischemic/leg ulcers. Beraprost was more efficacious in relieving CPAO symptoms and was better tolerated than ticlopidine. Beraprost may be useful for the treatment of patients with CPAO, but more studies are needed.     

噻吩并吡啶类抗血小板聚集药物研究概况

心脑血管疾病严重威胁人类健康,抗血小板治疗已经被证明可以有效预防和改善心脑血管疾病.噻吩并吡啶类药物是以二磷酸腺苷受体为靶点的一类抗血小板药物,包括噻氯匹定、氯吡格雷和普拉格雷,是目前临床上应用最为广泛、有效的抗血小板聚集、抗血栓药物,极大地改善了全球心脑血管患者的健康状况.概括介绍噻吩并吡啶类药物的代谢与起效模式、作用机制、临床应用及药物相互作用等方面的研究进展.