Platelet Aggregation Threshold Index Research Articles

The Inhibitory Effect of Platelet Aggregation Ability Assessed by the Platelet Aggregatory Threshold Index in a Patient with Recurrent Stent Thrombosis.

An 86-year-old man successfully underwent percutaneous coronary intervention (PCI), in which a drug-coated stent (DCS) was placed in the left anterior descending coronary artery. However, stent thrombosis occurred twice after eight and two months. After the second admission, the patient was tested for platelet aggregation activity using the platelet aggregation threshold index (PATI), and insufficient inhibition of platelet aggregation was observed. The patient's PATI improved to a satisfactory level using oral anticoagulants. At the six-month follow-up, clinical events were observed. Measuring the platelet aggregation ability can help clinicians understand the pathology of patients and determine treatment choices.

In vitro hemocompatibility investigation for the development of low-flow centrifugal blood pumps with less platelet clogging.

Low-flow blood pumps rated under 1 L/min are emerging for new medical applications, such as hemofiltration in acute use. In those pumps, platelet adhesion and aggregation have to be carefully considered because of clogging risk in the filter part. To find an acceptable hemocompatibility that can be applied to low-flow centrifugal blood pump design, the platelet aggregation index, clogging on a micromesh filter, and the hemolysis index were investigated using a low-flow blood pump designed for hemofiltration use. We conducted circulation testing in vitro using fresh porcine blood and two centrifugal pumps with different impeller inlet shapes. The Negative Log Platelet Aggregation Threshold Index (NL-PATI), which reflects the ability of residual platelets to aggregate, and flow rate were measured during reflux for 60 min, and the Normalized Index of Hemolysis (NIH (g/20 min)) was calculated. In addition, blood cell clogging after reflux was observed on the micromesh filter by SEM, and the adhesion rate was calculated. Our results showed that the platelet clogging on the micromesh filter occurred when the average NL-PATI was greater than 0.28 and the average NIH (g/20 min) was greater than 0.01. In contrast, platelet clogging on the micromesh was suppressed when NL-PATI was less than 0.17 and the NIH (g/20 min) was less than 0.003. These values might be used as acceptable hemocompatibility of low-flow centrifugal blood pumps with suppressed platelet clogging for hemofiltration pumps.

Influence of nonsteroidal anti-inflammatory drugs on aspirin\u2019s antiplatelet effects and suggestion of the most suitable time for administration of both agents without resulting in interaction

BackgroundLow-dose aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1) and suppresses platelet aggregation. It is effective for secondary prevention of cardiovascular events. Because nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly bind with COX-1, the antiplatelet effects of aspirin may be suppressed when NSAIDs are co-administered. This interaction could be avoided by avoiding simultaneous administration; however, the minimum interval that should separate the administration of aspirin and loxoprofen is not well known. In this study, we investigated how to avoid the influence of NSAIDs on the antiplatelet effects of aspirin. An in vitro experiment was performed to investigate the influence of ibuprofen and loxoprofen at various concentrations on aspirin’s antiplatelet action.MethodsPlatelet aggregation and thromboxane B2 (TXB2) levels were measured after addition of aspirin only and NSAIDs plus aspirin to platelet-rich plasma. NSAIDs were used at their maximum plasma concentrations, the assumed concentration after 6 h (for loxoprofen only), and the assumed concentration after 12 h of taking one clinical dose. Platelet aggregation threshold index (PATI), defined as the putative stimulus concentration giving 50% aggregation, was calculated as an index of aggregation activity.ResultsPATI decreased in ibuprofen plus aspirin group compared to that in the aspirin only group, regardless of ibuprofen concentration. Furthermore, PATI significantly decreased when aspirin was added after loxoprofen-trans-OH addition at the maximum concentration (4.1 ± 0.1 μg/mL), compared to that in aspirin only group (5.9 ± 0.1 μg/mL). PATI showed no significant difference after addition of loxoprofen at the assumed concentration after 6 h (aspirin only group, 5.0 ± 0.5 μg/mL; loxoprofen-trans-OH plus aspirin group, 4.9 ± 0.4 μg/mL).In addition, TXB2 concentration tended to decrease with increasing PATI.ConclusionsIt is desirable to avoid ibuprofen co-administration with the usual once-daily low-dose aspirin therapy; however, a 6-h interval between loxoprofen and aspirin could avoid this potential interaction when loxoprofen is taken before aspirin.

Utility of whole‐blood aggregometry for evaluating anti‐platelet therapy for Kawasaki disease

Anti-platelet therapy for Kawasaki disease (KD) is often done without monitoring drug efficacy. The aim of this study was to investigate the utility of whole-blood aggregometry to evaluate the efficacy of anti-platelet therapy for KD. Of 37 late-phase KD patients included in the present study, 20 were prescribed anti-platelet drugs. Platelet-rich plasma (PRP) aggregation with collagen as the stimulus was measured using an optical aggregometer. The area under the curve of small and large size aggregations was calculated, and categorized into five classes: -2, -1, 0, 1, and 2. Whole-blood aggregation with collagen or adenosine 5'-diphosphate (ADP) as stimulus was evaluated using the platelet aggregation threshold index (PATI), which is the concentration of stimulus that induces a whole-blood aggregation rate of 50%. In both collagen- and ADP-induced aggregation, there was a negative correlation between PATI and class determination using the PRP technique (collagen, rs = -0.870, P < 0.0001; ADP, rs = -0.620, P < 0.0001). Moreover, the PATI in collagen- and ADP-induced aggregation was significantly higher in the anti-platelet drug therapy group than in the untreated group (collagen, P < 0.0001; ADP, P = 0.0002). The serum thromboxane B2 level in the anti-platelet drug therapy group was also significantly lower than that in the untreated group (P < 0.0001). PATI was significantly higher in those treated with thienopyridine drug combinations than those without drug therapy (P = 0.0036). Whole-blood aggregometry is useful for monitoring the efficacy of anti-platelet therapy for KD.

Impact of proton pump inhibitors or famotidine on the antiplatelet actions during dual-antiplatelet therapy in Japanese patients

It has been reported that the antiplatelet action becomes attenuated when a proton pump inhibitor is used in combination with clopidogrel. The effect of an antacid causing platelet aggregation during the administration of clopidogrel was investigated. The subjects consisted of 265 patients with coronary artery disease. Platelet aggregation function testing (light transmittance aggregometry) was conducted while aspirin and clopidogrel 75mg were taken orally and the minimum concentration of aggregation induction platelet aggregation threshold index was measured. The ADP-PATI, measured with ADP as the inducing substance, was compared and investigated according to the type of concomitantly used antacid. The results of the ADP-PATI were: control group: 3.47±0.95μM (N=67), famotidine group: 3.80±0.52μM (N=32), rabeprazole group: 3.43±0.93μM (N=87), lansoprazole group: 3.28±1.04μM (N=63) and omeprazole group: 3.33±0.81μM (N=16). No statistically significant difference was observed regarding the ADP-PATI of respective groups compared to the control group. The concomitant use of famotidine, rabeprazole, lansoprazole, and omeprazole did not affect the antiplatelet action of clopidogrel in Japanese patients.

Impact of Platelet Reactivity to Adenosine Diphosphate Before Implantation of Drug-Eluting Stents on Subsequent Adverse Cardiac Events in Patients With Stable Angina

Diverse pharmacological effects of anti-platelet thienopyridines due to individual differences in metabolism have been reported. However, an association between on-treatment platelet reactivity and adverse ischemic events after drug-eluting stent (DES) implantation in Japanese patients has not been fully elucidated. A total of 450 consecutive patients on dual anti-platelet therapy (aspirin and ticlopidine) with stable angina who underwent DES implantation were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation was measured before DES implantation using the screen filtration pressure method. The ADP concentration necessary for 50% aggregation was designated as the platelet aggregation threshold index (PATI). A composite primary endpoint of cardiac death, myocardial infarction, target lesion revascularization (TLR), and stent thrombosis occurring within 1 year after stenting, was evaluated. A PATI value <4.8 µmol/L was defined as high on-treatment reactivity to ADP. The composite primary endpoint occurred in 55 patients (12.2%) in the 1-year-period after DES implantation, and the prevalence was 19.0% and 5.1% in groups with high and low on-treatment reactivity to ADP, respectively, showing a significantly higher prevalence in the high reactivity group (P<0.001). The main event was TLR (18.1% vs. 5.1%, P<0.001). These data suggested that high on-treatment platelet reactivity to ADP and subsequent occurrence of adverse ischemic events (particularly TLR) were correlated in patients with stable angina who underwent DES implantation.

Measuring Platelet Aggregation in Dialysis Patients With a Whole Blood Aggregometer by the Screen Filtration Pressure Method

A semi-automatic, whole-blood aggregometer based on the screen filtration pressure (SFP) method is now widely used clinically and in research, but has not been used with hemodialysis (HD) patients. We measured whole-blood platelet aggregation in HD patients by the SFP method. This retrospective cross-sectional study included 62 HD patients, of whom 47 were non-diabetic and 15 were diabetic; we also included a control group of healthy, non-uremic subjects. With the t-test, we examined differences in the platelet aggregation threshold index (PATI) in meaningful sub-groupings of the HD patients, depending on whether or not they had diabetes, and whether or not they had been given antiplatelet agents. Considering the non-diabetic HD patients first, their PATI values were significantly higher than those values in the control subjects (3.1 [1.0-5.2] vs. 1.8 [1.3-2.3] µM, P<0.001). The non-diabetic HD patients taking antiplatelet agents showed significantly (1.9 times) higher PATI values than the non-diabetic HD patients without antiplatelet agents (4.4 [1.8-7.0] vs. 2.3 [1.3-3.3] µM, P=0.003). We observed similar trends among diabetic HD patients. Whole-blood analysis by the SPF method seems to be a promising way of monitoring platelet function for HD patients.

Enhanced platelet activation following coronary stent implantation in patients on hemodialysis

Hemodialysis ("HD") has been suggested as a risk factor for stent thrombosis. However, platelet function in HD patients after coronary stent implantation remains unclear. The aim of this study was to evaluate platelet function following coronary stent implantation in HD patients. A total of 10 HD and 31 non-HD patients who underwent a first coronary stent implantation were studied. All patients received 100 or 200mg of asprin and thienopiridine (either ticlopidine 200mg or clopidogel 75mg) daily. Platelet function was assessed 2-6weeks (21±8days) after stent implantation by: (1) platelet maximal aggregation, using light transmittance aggregometry; (2) platelet aggregation threshold index, which was defined as putative concentration of agonist giving 50% maximum aggregation using whole-blood aggregometry; and (3) platelet activation markers (PAC-1 and CD62p), using whole blood flow cytometry. There were no differences between the two groups in baseline and procedure characteristics, except for a greater prevalence of hypertension and calcification in the HD group. Early stent thrombosis and bleeding did not occur in either group. Although no differences in platelet maximal aggregation or whole-blood aggregation were observed, expression of PAC-1 (39.6±9.1 vs 24.2±13.2%) and CD62p (10.4±5.5 vs 5.4±2.3%) were significantly increased in the HD group compared with the non-HD group. HD patients exhibited enhanced platelet activation after coronary stent implantation, but suppression of platelet aggregation was achieved by the current dual antiplatelet therapy.

アスピリンの抗血小板作用に及ぼす非ステロイド性抗炎症薬の影響に関する研究―ヒト血液添加実験系を用いた検討―

Low dose aspirin acts as an antiplatelet agent through irreversible acetylation of platelet cyclooxygenase (COX)-1,which inhibits platelet aggregation.Nonsteroidal anti-inflammatory drugs (NSAIDs) have a similar mechanism of action to aspirin,and may interact pharmacodynamically with it.In view of this,we performed an in vitro experimental study in which 6 NSAIDs with various COX-1 activities were added to human blank blood to investigate the influence of each one on the antiplatelet action of aspirin.Platelet rich plasma (PRP) was obtained from 8 healthy volunteers (23.3±3.2 years old).After adding aspirin (plasma concn.: 16μg/mL) and NSAIDs (plasma concn.: maximal concentration in clinical use) to the PRP,aggregation was measured using collagen as the stimulus.We used the platelet-aggregation threshold index (PATI) as the index of aggregation activity for this study.The PATI of a group in which aspirin was added after ibuprofen (Ibu→Asp) and that of a group in which both drugs were added at the same time (Asp+Ibu) were 3.54±0.80 and 3.53±1.01μg/mL,respectively.These were lower than the PATI for aspirin alone (5.17±1.18μg/mL),indicating interference with the antiplatelet effect by the NSAID.For the other 5 NSAIDs,the PATI obtained was similar to that for aspirin,regardless of the order of addition.The logarithmic value of the unbound drug concentration of each NSAID (Df) divided by platelet COX-1 IC50[log (Df/COX-1 IC50)]was correlated with its PATI (R=0.817,p<0.001),suggesting that the interaction between low dose aspirin and NSAIDs may be inferred from the level of inhibition of platelet COX-1 at clinical drug concentrations.

Action of Aspirin on Whole Blood-Aggregation Evaluated by the Screen Filtration Pressure Method

There are few monitoring systems widely used in clinical practice for evaluating the effectiveness of aspirin therapy, so in the present study aspirin's antiplatelet effects we investigated with a whole blood aggregometer using a screen filtration pressure (SFP) method. Thirty-five healthy male volunteers took 100 mg/day aspirin for 14 days. Whole-blood aggregation was analyzed at baseline and on days 7 and 14, using collagen and adenosine diphosphate as the stimuli, and compared with the platelet-rich plasma (PRP) aggregation measured by optical aggregometer. The platelet-aggregation threshold index (PATI) for both methods, which was defined as the putative agonist-concentration giving half-maximal aggregation, and the PRP-maximal aggregation rate were analyzed. The maximal aggregation rate induced by 1.6 mg/L collagen decreased from 85.5% (80.8-92.8) [median (interquartile range)] at baseline to 51.5% (39-63.8) on day 14 (p<0.0001). The PRP-PATI and whole-blood PATI for collagen increased from 0.32 (0.28-0.70) to 1.82 mg/L (1.25-2.89) (p<0.0001) and from 0.28 (0.22-0.3) to 1.06 mg/L (1.01-1.29) (p<0.0001) respectively. The whole-blood PATI and PRP-PATI for collagen, as well as the maximal PRP aggregation rate, clearly distinguish platelet aggregability before and after aspirin intake. However, whole-blood analysis by the SFP-method is easier to perform, and is a promising method of monitoring aspirin's effects.

Abstract 2174: Increased Platelet Aggregability In Obstructive Sleep Apnea Syndrome Patients Is Improved By Nasal Continuous Positive Airway Pressure Treatment

Background and aim: Obstructive sleep apnea (OSA) is a risk factor for cerebrovascular diseases. One cause for them is an occlusive arterial thrombus triggered by local platelet activation. Whether OSA is an independent risk factor for increased platelet aggregability is unclear. Methods: We enrolled 124 patients with snoring or daytime sleepiness in whom 3% oxygen desaturation index (3%ODI), a principal marker of the severity of intermittent hypoxia and reoxygenation (IHR), was measured. We studied ex vivo ADP- and collagen-induced aggregation of platelet-rich plasma using an optical aggregometer. The agonist concentration giving half maximal aggregation was defined as the platelet-aggregation threshold index (PATI) value. Therefore, the lower PATI value implicates the higher aggregability. In 23 patients who underwent nasal CPAP, platelet aggregability was followed until 90 days. Results: There was a significant difference in the PATI value for ADP-induced aggregation between 66 patients with non-to-mild OSA (3%ODI≤15) (1.04±0.07 μM, mean±SE) and 58 patients with moderate-to-severe OSA(3%ODI&gt;15) (0.78±0.09 μM)(p=0.029). Multiple linear model revealed that 3%ODI strongly significantly contributed to the PATI values for ADP (p&lt;0.001) and collagen (p=0.0026) among the 59 subjects with a cardiovascular risk factor such as smoking, hypertension, diabetes mellitus or hyperlipidemia. However, the percentage of time of arterial O2 saturation&lt;90% during sleep did not significantly contribute to the PATI values for ADP (p=0.21) and collagen (p=0.20). After initiation of nasal CPAP therapy, the PATI values for ADP-induced aggregation significantly worsened transiently on day 30 (p=0.035), and then it recovered and improved at day 90 and the PATI for collagen-induced aggregation improved at day 90 without the transient exacerbation. Conclusions: OSA patients had increased platelet aggregability. Severity of IHR more significantly contributed to platelet aggregation than total hypoxic time. Among OSA patients with conventional cardiovascular risk factors, the effects of IHR on the platelet aggregability was prominent. Nasal CPAP initially induced a transient hyperaggregable state of platelets, after which it continued to improve.

Genetic strain differences in platelet aggregation of laboratory mice

To investigate the physiological role of novel genes and proteins in platelet activation, various knockout mice have been produced. A number of standard inbred mouse strains each possessing genetically unique characters such as high tumor generation, hyperglycemia or hyperlipidemia, have been bred. In breeding knockout mice for investigation of specific physiological functions, appropriate selection of parental or backcross strains is necessary. Thus, examination of strain-specific platelet characteristics is important. In the present study, platelet aggregation responses of 13 laboratory mouse strains, 129/Sv, A, AKR, BALB/c, C3H/He, C57BL/6J, CBA, DBA/1, DBA/2, ddY, FVB, ICR, and NZW, and the diabetic strain C57BL/KsJ db/db, were compared. Marked strain differences were observed in ADP- and collagen-induced platelet aggregation. The highest responses with both were seen in AKR/J and NZW/N, whereas the lowest were seen in DBA/2 and DBA/1. There was a 5-fold difference in the platelet aggregation threshold index (PATI) for ADP-induced PRP aggregation between AKR/J (0.6 microM) and DBA/2 (3.0 microM). With whole blood aggregation, the highest response was seen in AKR, whereas the lowest was seen in DBA/2 and DBA/1. The present study demonstrated that there is considerable strain difference in platelet aggregation among laboratory mice, which should be taken into account in backcrossing knockout strains.

Changes in platelet aggregation during cardiopulmonary bypass: comparison of poly-2-methoxyethylacrylate and heparin as a circuit coating material

At present, there are various biomaterials that have high biocompatibility. In particular, there are many types of coated circuits in cardiopulmonary bypass (CPB) systems. However, only a few clinical studies have investigated platelet aggregation caused by these coated circuits. In this study, a CPB system coated with poly-2-methoxyethylacrylate (X coating) was used to ascertain whether platelet aggregation could be suppressed during CPB, and a comparison was made between X coating and ordinary (covalently bonded) heparin coating. The subjects were 19 adult patients who were scheduled to undergo valve replacement or valvuloplasty. They were divided into two groups: group X (X coating) and group H (heparin coating). The platelet aggregation threshold index (PATI, grading curve) and beta-thromboglobulin and plalelet factor IV levels were assessed preoperatively (control), 5 min after heparin administration, 10 and 60 min after the start of CPB, and 0 and 2 h after the end of CPB. The results indicated that platelet aggregation was reduced during CPB and that platelets were activated. The changes in platelet aggregation associated with the X coating were shown to be similar to those associated with heparin coating.

Characterization of platelet aggregation in whole blood of laboratory animals by a screen filtration pressure method

The characteristics of platelet aggregation of laboratory animals were investigated with whole blood and platelet-rich plasma (PRP). We measured the platelet aggregation threshold index (PATI) of whole blood and PRP aggregations induced by ADP or collagen, using a novel whole blood aggregometer, the WBA analyzer, with a screen filtration pressure (SFP) method. At 60 min after blood collection, PATI values of guinea pig, mouse, rat, dog and rabbit were 0.83, 1.78, 46.48, 49.85 and 53.42 μM for ADP-induced whole blood aggregation, respectively, whereas their PATI values for ADP-induced PRP aggregation were 1.16, 2.77, 2.65, 10.81 and 18.77 μM, respectively. These suggest that ADP-induced platelet aggregations of rat, dog and rabbit are suppressed in whole blood. PATI values of guinea pig, mouse, rat, dog and rabbit were 1.84, 0.62, 11.90, 2.34, 12.32 μg/ml for the collagen-induced whole blood aggregation, respectively, whereas their PATI values for the collagen-induced PRP aggregation were 4.21, 1.50, 5.36, 11.31, 13.30 μg/ml, respectively. Collagen-induced aggregation activity of the guinea pig, mouse and dog was significantly higher in whole blood than in the PRP. These results demonstrated that species differences in laboratory animals exist for whole blood aggregation, and that the SFP aggregometer may be useful to evaluate platelet function in various animal species.

Estimation of anti-platelet drugs on human platelet aggregation with a novel whole blood aggregometer by a screen filtration pressure method.

1. The effects of anti-platelet drugs on human whole blood aggregation were evaluated using a novel whole blood aggregometer by a screen filtration pressure (SFP) method. 2. The SFP whole blood aggregometer was found to successfully detect whole blood aggregation induced by ADP, collagen and TRAP by measuring the SFP of blood samples. The platelet aggregation threshold index (PATI), the concentration of agonist required with an inducing pressure rate of 50%, varied time-dependently after collection of blood. High values for ADP and collagen were noted immediately after blood collection, suggesting low aggregation activity of platelets, and gradually increase thereafter. 3. Cilostazol (phosphodiesterase 3 inhibitor), dipyridamole, aspirin and tirofiban all inhibited whole blood aggregation in vitro. Inhibitory effects of cilostazol and dipyridamole, but not tirofiban, were markedly enhanced 6 or 7 fold by long pre-incubation (60 min), compared with short pre-incubation (2 min). Such enhancement was only observed with ADP- and not collagen-induced whole blood aggregation. A similar phenomenon was also observed for aggregation with platelet rich plasma (PRP). Cilostazol inhibition of ADP-induced platelet aggregation was more potent with PRP than whole blood (PATI(200)=3.80+/-0.95 microM for whole blood; 2.04+/-0.61 microM for PRP). Inhibitory effects of dipyridamole were attenuated in PRP without erythrocytes. 4. These results demonstrate that the SFP aggregometer can sensitively detect anti-platelet aggregatory effects of various kinds of drugs. So that it is a useful tool for evaluation of anti-platelet drugs.