Thrombogenicity In Patients Research Articles

Malnutrition-associated high bleeding risk with low thrombogenicity in patients undergoing percutaneous coronary intervention

Background and aimsAlthough antithrombotic treatments are established for coronary artery disease (CAD), they increase the bleeding risk, especially in malnourished patients. The total thrombus-formation analysis system (T-TAS) is useful for the assessment of thrombogenicity in CAD patients. Here, we examined the relationships among malnutrition, thrombogenicity and 1-year bleeding events in patients undergoing percutaneous coronary intervention (PCI). Methods and resultsThis was a retrospective analysis of 300 consecutive CAD patients undergoing PCI. Blood samples obtained on the day of PCI were used in the T-TAS to compute the thrombus formation area under the curve. We assigned patients to two groups based on the geriatric nutritional risk index (GNRI): 102 patients to the lower GNRI group (≤98), 198 patients to the higher GNRI group (98<). The primary endpoint was the incidence of 1-year bleeding events defined by Bleeding Academic Research Consortium criteria types 2, 3, or 5. The T-TAS levels were lower in the lower GNRI group than in the higher GNRI group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the lower GNRI group compared with the higher GNRI group. The combined model of the GNRI and the Academic Research Consortium for High Bleeding Risk (ARC-HBR) had good calibration and discrimination for bleeding risk prediction. In addition, having a lower GNRI and ARC-HBR positivity was associated with 1-year bleeding events. ConclusionA lower GNRI could reflect low thrombogenicity evaluated by the T-TAS and determine bleeding risk in combination with ARC-HBR positivity.

Temporary Rise in Blood Thrombogenicity in Patients with Acute Myocardial Infarction.

Objective Although blood thrombogenicity seems to be one of the determinant factors for the development of acute myocardial infarction (MI), it has not been dealt with in-depth. This study aimed to investigate blood thrombogenicity and its change in acute MI patients. Methods and Results We designed a prospective, observational study that included 51 acute MI patients and 83 stable coronary artery disease (CAD) patients who underwent cardiac catheterization, comparing thrombogenicity of the whole blood between: (1) acute MI patients and stable CAD patients; and (2) acute and chronic phase in MI patients. Blood thrombogenicity was evaluated by the Total Thrombus-Formation Analysis System (T-TAS) using the area under the flow pressure curve (AUC 30 ) for the AR-chip. Acute MI patients had significantly higher AUC 30 than stable CAD patients (median [interquartile range], 1,771 [1,585–1,884] vs. 1,677 [1,527–1,756], p = 0.010). Multivariate regression analysis identified acute MI with initial TIMI flow grade 0/1 as an independent determinant of high AUC 30 ( β = 0.211, p = 0.013). In acute MI patients, AUC 30 decreased significantly from acute to chronic phase (1,859 [1,550–2,008] to 1,521 [1,328–1,745], p = 0.001). Conclusion Blood thrombogenicity was significantly higher in acute MI patients than in stable CAD patients. Acute MI with initial TIMI flow grade 0/1 was significantly associated with high blood thrombogenicity by multivariate analysis. In acute MI patients, blood thrombogenicity was temporarily higher in acute phase than in chronic phase.

Ethnic Difference of Thrombogenicity in Patients with Cardiovascular Disease: a Pandora Box to Explain Prognostic Differences.

Arterial and venous atherothrombotic events are finely regulated processes involving a complex interplay between vulnerable blood, vulnerable vessel, and blood stasis. Vulnerable blood ('thrombogenicity') comprises complex interactions between cellular components and plasma factors (inflammatory, procoagulant, anticoagulant, and fibrinolytic factors). The extent of thrombogenicity may determine the progression of atheroma and the clinical manifestation of atherothrombotic events, with the highest thrombogenicity in African Americans and lowest in East Asians. Inherent thrombogenicity may influence clinical efficacy and safety of specific antithrombotic treatments in high-risk patients, which may in part explain the observation that East Asian patients have reduced anti-ischemic benefits and elevated bleeding risk with antithrombotic therapy compared to Caucasian patients. In this review, we discuss available evidence regarding the racial differences in thrombogenicity and its impact on clinical outcomes among patients with atherosclerotic cardiovascular disease.

Formalised assessment of systemic thrombogenicity in patients with Polycythemia vera suffered an ischemic stroke

Introduction. Thrombosis diagnosis and prevention in patients with Polycythemia vera (PV) suffered an ischemic stroke (IS) are still open. The aim was to find the reasons for systemic thrombogenicity and to compare the applicability of the main scales assessing thrombosis risk in patients with PV suffered IS.Materials and methods. We followed up 127 people (42-75 y.o.), of which 68 were patients with PV suffered IS (group I) and 59 non-PV-patients with ischemic stroke (group II). Clinical study included common blood analysis, rheological properties of erythrocytes, coagulation and endothelial parameters, cytokines, inflammation markers, angiogenesis markers, and testing for the V617F mutation in the JAK2 gene. The follow up included common and neurological examinations as well, and the assesment of thrombosis risk factors with both Caprini scale and CHA2DS2-VASc scale. All patients were examined twice as in the acute period of IS as well as in 16-18 months.Results. Between the groups no significant differences were found for the NIHSS average score and for Bartel index as well.The Caprini score belonged to the “very high risk” (score &gt; 6) in both groups in the acute period of IS. At the same time, the score “8-10 points” prevailed in group II (68%) whereas the score “11-12 points” prevailed in group I.In the acute time of IS the CHA2DS2-VASc score revealed 12% of patients from both groups who had a score of “3-4 points” (moderate risk of thrombosis).In group I thrombotic complications rate correlated significantly with the JAK2V617F gene allelicloading (r = 0.236; p &lt; 0.05), and the development of recurrence cerebrovascular disorders correlated significantly with Caprini score (r = 0.241; p &lt; 0.05), but not with CHA2DS2-VASc score.Aiming to predict thrombotic complications in PV-patients the threshold (cut off) points were established for those markers as factor VIII, factor VII, red blood cell deformability, thrombin activated fibrinolysis inhibitor (TAFI), red blood cell count, white blood cell count, t-PA, VEGF-A, p-thrombomodulin, and ADAMTS-13.This pattern of parameters showed the odds ratio of thrombotic complications 10.3 (95% CI 7.6-13.8) in PV-patients in thelong-term period.At the end of the follow up the Caprini score showed a trend towards a decreasing in total while the CHA2DS2-VASc score remained virtually unchanged.Conclusion. We assume the accurate assessment of thrombotic risk in patients with Polycythemia vera suffered an ischemic stroke requires a proposed pattern of parameters including the test for JAK2V617F allelicloading and the calculation of Caprini score but not CHA2DS2-VASc score. Final results may provoke to change standard antithrombotic therapy in those patients towards its intensification due to pathogenetic featues of cancer-associated thrombosis.

A modified microchip-based flow chamber system for evaluating thrombogenicity in patients with thrombocytopenia

BackgroundIn the intensive care unit (ICU), patients with thrombocytopenia are at high risk for bleeding and should be assessed for their thrombogenic potential. However, the analytical conditions of conventional hemostatic tests are unsuitable for the evaluation of low-platelet samples. Here we aimed to establish suitable analytical conditions with the Total Thrombus-formation Analysis System (T-TAS) for quantitative assessment of thrombogenic potential in patients with thrombocytopenia and to investigate how T-TAS values relate to bleeding symptoms and the effects of platelet transfusion.MethodsModified chips with a different chamber depth were developed for the analysis of low-platelet samples in the T-TAS. We included 10 adult patients admitted to the ICU of Kagoshima University Hospital who required platelet transfusion. Patients were divided into major and minor bleeding groups according to their bleeding scale before platelet transfusion. The thrombogenic potential of these patients before and after platelet transfusion was assessed with hemostatic function tests, including rotational thromboelastometry, multiplate aggregometry, and the T-TAS.ResultsAnalysis of low-platelet samples revealed that, compared with the conventional chip (80-μm-deep chamber), the modified chip (50-μm-deep chamber) achieved higher sensitivity in detecting elevation of flow pressure caused by growth of an occlusive thrombus in the T-TAS analytical chamber. All patients in the minor bleeding group retained thrombogenic potential that occluded the modified chip (occlusion time 16.3 ± 3.3 min), whereas most patients in the major bleeding group were unable to occlude the modified chip during the 30-min measurement (P < 0.01). The recovery of thrombogenic potential after platelet transfusion was confirmed with the T-TAS and correlated with the function, rather than the count, of transfused platelets. Among all evaluated parameters in hemostatic function tests, only the T-TAS showed significant differences in occlusion time and area under the curve both between the minor and major bleeding groups and between pre- and post-platelet transfusion.ConclusionsWe developed a modified microchip-based flow chamber system that reflects the hemostatic function of patients with thrombocytopenia.

Association of lipoprotein(a) with platelet aggregation and thrombogenicity in patients undergoing percutaneous coronary intervention

This study aimed to evaluate the association of lipoprotein(a) levels with platelet aggregation and thrombogenicity in patients undergoing percutaneous coronary intervention (PCI), and to investigate the ischemic outcome on this population. Lipoprotein(a) and modified thrombelastography were measured in 6601 consecutive patients underwent PCI on dual antiplatelet therapy. Cox proportional regression analysis was applied to illustrate the ischemic events in a 2-year follow up. The mean levels of lipoprotein(a) were 29.0 mg/dl. Patients with higher lipoprotein(a) levels had significantly accelerated fibrin generation (lower K time and bigger α angle) and greater clot strength (higher maximum amplitude (MA)) than patients with lower lipoprotein(a) levels (P < .001). Moreover, the higher lipoprotein(a) group also exhibited significantly higher adenosine diphosphate (ADP) induced platelet aggregation (MAADP) by thrombelastography platelet mapping assay than lower lipoprotein(a) group. Cox regression analyzes revealed that patients with higher lipoprotein(a) levels had a 16% higher risk of major adverse cardiovascular and cerebrovascular events (HR 1.159, 95%CI: 1.005–1.337, P = .042) compared with patients with lower lipoprotein(a) levels. This association persisted after adjustment for a broad spectrum of risk factors (HR 1.174, 95%CI: 1.017–1.355, P = .028). High plasma lipoprotein(a) levels were associated with increased platelet aggregation and ischemic events in patients underwent PCI. Lipoprotein(a) might indicate the need for prolonged antiplatelet therapy.

Тромбогенность у больных ишемическим инсультом на фоне истинной полицитемии

Thrombogenicity and its causes in patients with ischemic stroke (IS) and pre-existing polycythemia vera (PV) is a significant clinical concern. The aim of this study was to identify the range of factors associated with increased thrombogenicity in patients with IS and pre-existing PV. We performed a physical examination and laboratory tests on 127 patients in the hyperacute stroke stage and 16-18 months after. Of them, 68 patients had PV (the main group) and 59 did not have this condition (the comparison group). Laboratory tests were conducted to evaluate blood rheology, hemostasis, endothelial function, angiogenesis, proinflammatory cytokine levels; we also tested patients for the presence of the V617F mutation in the JAK2 gene and analyzed the contribution of all studied parameters to the development of thrombotic and hemorrhagic complications. We found that the neurological picture did not differ between the groups: mean NIHSS scores were 12 and 13 points, respectively. Morphological and functional characteristics of red blood cells and platelets, hemostasis and cytokine profiles were compared between patients with IS and pre-existing PV and the comparison group. One of the key elements in potentiating thrombotic complications in patients with IS and PV was JAK2 V617F allele burden. The obtained data suggest the cumulative effect of the identified factors promoting thrombus formation in post-stroke patients with PV and overpowering the effect of antiplatelet therapy.

The effects of wheatgrass juice administration in colon cancer patients during adjuvant chemotherapy and the treatment reflection on the extracellular vesicles.

e23045 Background: Adjuvant chemotherapy is recommended in stage II-III colorectal cancer (CC). Wheatgrass juice (WGJ), has high nutritional values may attenuate chemotherapy adverse events (AE). Extracellular vehicles (EVs) are subcellular membrane blebs that provide information on cellular processes. Aim: To evaluate the incidence of chemotherapy AE and to elucidate the effects of supportive treatment of WGJ on CC patients’ EVs characteristics. Methods: In a prospective trial between 3/2014- 7/2017, 99 patients stage II-III CC, treated with standard adjuvant chemotherapy were enrolled. According to patient preference, they were divided into: control group of 50 (CC-C) patients and intervention group of 49 patients who received chemotherapy plus consumption of daily 60cc frozen WGJ (CC-W). EVs were isolated from the blood samples of 15 healthy controls (HC) and 25 patients from each study group. Blood samples were taken before, during and at the end of chemotherapy, EVs characterized by membrane antigens/cytokine content Results: Study groups were well balanced. Median follow-up time was 15 months. Eleven patients had died at the time of analysis, 3 in the WGJ and 8 in the control ( p= 0.142). 11/50 (22%) and 8/49 (16.3%) had severe diarrhea in the control and WGJ groups, respectively ( p= 0.47). There was no difference between the groups in RFS (HR = 1.19 , p= 0.69). Higher levels of endothelial EVs (CD34+41, CD144), indicating vascular injury, were found in CC-C patients- compared to CC-W during and at the end of treatment. Increased EVs thrombogenicity in patients was documented, while EVs thrombogenicity was lowered in CC-W compared to CC-C during or at the end of treatment (TF, P = 0.029; TF/TF-pathway inhibitor (TFPI) ratio, p = 0.008; endothelial protein C receptor 0.005 and annexin-V 0.05). Following treatment, the majority of growth-factors/pro-inflammatory cytokines were found to be lower in CC-W than in CC-C. Conclusions: Daily consumption of WGJ during chemotherapy may reduce vascular damage and thrombogenicity. There was no statistical difference in overall survival. However, the large difference in death rate may relate to other long-standing effects of daily WGJ consumption. Clinical trial information: NCT01991080.

Comparison of diverse platelet activation markers as indicators for left atrial thrombus in atrial fibrillation

Atrial fibrillation (AF) is well known for being a major risk factor of thromboembolic stroke. We could recently demonstrate an association of monocyte–platelet aggregates (MPAs) with the degree of thrombogenicity in patients with AF. This study investigated platelet activation markers, as potential biomarkers for the presence of left atrial (LA) thrombus in patients with AF. One hundred and eight patients with symptomatic AF underwent transesophageal echocardiography (TEE) before scheduled cardioversion or pulmonary vein isolation. In order to determine the content of MPAs by flow-cytometric quantification analyses, blood was drawn on the day of TEE. The soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were obtained by Cytometric Bead Arrays (CBA). D-dimer levels were detected by quantitative immunological determination of fibrin degradation products. Clinical, laboratory, and echocardiographic standard parameters were obtained from all patients, including the determination of the flow in the left atrial appendage (LAA). Patients with detected LA thrombus (n = 28) compared with patients without thrombus (n = 80) showed an increased number of common risk factors, such as age, diabetes, heart failure, and coronary artery disease (CAD). The presence of LA thrombus was associated with significantly increased levels of MPAs (147 ± 12 vs. 304 ± 29 per µl; p < 0.00), sCD40L (106.3 ± 31.0 vs. 33.5 ± 2.1 pg/ml, p = 0.027), and D-dimer (0.13 ± 0.02 vs. 0.69 ± 0.21 mg FEU/l, p = 0.015). In contrast, sP-selectin showed no association with LA thrombus. A multivariate regression analysis showed that MPAs, sCD40L as well as D-dimers were independent indicators for the existence of LA thrombus. MPAs above 170 cells/µl indicated LA thrombus with a high sensitivity of 93% and a specificity of 73% (OR 62, 95% CI. 6.9–557.2, p < 0.001) in patients with AF, whereas the D-dimer lost their quality as independent indicator by using the conventional cut-off of 0.5 mg/l within the regression analysis. MPAs, as well as the D-dimer, correlated significantly negatively with the flow in the LAA measured during TEE. The content of MPAs, sCD40L, and D-dimer, but not sP-selectin showed an increased dependence on LA thrombus in patients with AF. In our study group, MPAs showed the best diagnostic test accuracy of the compared platelet markers. The different results of the examined platelet activation markers could be an indication of diverse mechanisms of LA thrombus in AF. Further studies should evaluate whether determination of MPAs in clinical routine may suffice to indicate the presence of LA thrombus in patients with AF.

Antiplatelet Therapy Combinations and Thrombogenicity in Patients with Non-Valvular Atrial Fibrillation.

Background and ObjectivesCombination antiplatelet therapy reduces the risk of ischemic stroke compared with aspirin monotherapy in non-valvular atrial fibrillation (NVAF) patients. The underlying mechanism, however, remains unclear. In addition, the association between platelet inhibition and thrombogenicity in NVAF has not been evaluated.Subjects and MethodsWe randomized 60 patients with NVAF that were taking 100 mg of aspirin daily (>1 month) to adding 75 mg of clopidogrel daily (CLPD group), 100 mg of cilostazol twice daily (CILO group), or 1000 mg of omega-3 polyunsaturated fatty acid twice daily (PUFA group). Biomarkers (von Willebrand factor antigen [vWF:Ag], fibrinogen, D-dimer, and high-sensitivity C-reactive protein [hs-CRP]) and platelet reactivity (PR), which were the levels stimulated by adenosine diphosphate (ADP), thrombin-receptor agonist peptide, collagen, and arachidonic acid, were measured at baseline and 30-day follow-up.ResultsCombination antiplatelet therapy significantly reduced vWF:Ag and fibrinogen levels (7.7 IU/dL, p=0.015 and 15.7 mg/dL, p=0.005, respectively), but no changes were found in D-dimer and hs-CRP levels. The CLPD and CILO groups showed fibrinogen and vWF:Ag level reductions (24.9 mg/dL, p=0.015 and 9.3 IU/dL, p=0.044, respectively), whereas the PUFA group did not show any differences in biomarkers. Irrespective of regimen, the changes in fibrinogen and vWF:Ag levels were mainly associated with the change in ADP-mediated PR (r=0.339, p=0.008 and r=0.322, p=0.012, respectively).ConclusionIn patients with NVAF, combination antiplatelet therapy showed reductions for vWF:Ag and fibrinogen levels, which may be associated with the inhibitory levels of ADP-mediated PR. The clinical implications of these findings need to be evaluated in future trials.

Measurement of residual platelet thrombogenicity under arterial shear conditions in cerebrovascular disease patients receiving antiplatelet therapy

Essentials A consensus methodology for assessing the effects of antiplatelet agents has not been established. Measuring platelet thrombus formation (PTF) for evaluating antiplatelet effects was assessed. PTF differentially reflected antiplatelet effects compared to other tests. PTF may be associated with the severity of carotid or intracranial arterial stenosis. Click to hear a presentation on platelet function testing in the clinic by Gresele and colleagues Background A consensus methodology for assessing the effects of antiplatelet agents has not been established. Objective We investigated the usefulness of directly measuring platelet thrombus formation (PTF) using a microchip-based flow chamber system for evaluating antiplatelet therapy. Patients/Methods Platelet thrombus formation in the whole blood of 94 patients with ischemic cerebrovascular disease treated with clopidogrel and/or aspirin was measured in a flow chamber system at a shear rate of 1500 s(-1) and was compared with the results of assays for agonist-induced platelet aggregability, phosphorylation of vasodilator-stimulated phosphoprotein, platelet p-selectin expression (PS), and platelet-monocyte complexes. Results In all patients tested, area under the flow pressure curve (AUC10), which represents platelet thrombogenicity, showed weak correlation with platelet aggregation induced by either adenosine diphosphate or collagen. In addition, AUC10 was lower in patients treated with dual antiplatelet therapy (median 79.4) compared with patients treated with aspirin or clopidogrel alone (217.7 and 301.0, respectively), whereas the parameters evaluated by the other assays did not reflect the combined treatment efficacy. In clopidogrel monotherapy patients, AUC10 was associated with the severity of arterial stenosis (R(2) = 0.127, β = 1.25), and AUC10 and PS were higher in patients with severe carotid or intracranial arterial stenosis than in those with mild stenosis. Conclusions Platelet thrombus formation measurement using a flow-chamber system was useful for evaluating the efficacy of treatment with aspirin and clopidogrel, both alone and in combination. The present findings indicate that high residual platelet thrombogenicity in patients treated with clopidogrel may be associated with the severity of carotid or intracranial arterial stenosis.

Abstract 13988: Novel Quantitative Assessment of Whole Blood Thrombogenicity in Patients Treated With Anticoagulants Undergoing Radiofrequency Catheter Ablation for Atrial Fibrillation

Introduction: Non-vitamin K antagonist oral anticoagulants (NOACs) are equivalent to warfarin in preventing thromboembolism in patients with atrial fibrillation (AF). Recently, Total Thrombus-formation Analysis System (T-TAS) was developed as an easy-to-use system for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, PL chip; collagen plus tissue factor, AR chip). Hypothesis: We evaluated the efficacy and safety of NOACs using the T-TAS in AF patients undergoing radiofrequency catheter ablation (RFCA). Methods: After exclusion of 19 from 121 consecutive patients undergoing RFCA for AF, the remaining 102 patients were divided into two groups; AF patients treated with warfarin (n=28), and NOACs (n=74). Blood samples obtained on the day (anticoagulant-free point), 3 days and 1 month after RFCA were used in T-TAS to compute the thrombus formation area under the curve (AUC) (PL24-AUC10, AUC for PL chip; AR10-AUC30, for AR chip). Results and Conclusion: The AR10-AUC30 and PL24-AUC10 levels were identical between the warfarin and NOACs groups on the day of RFCA (1708.5±162.1 vs 1757.5±138.0 in AR10-AUC30, p=0.13 and 389.1±95.5 vs 391.7±76.0 in PL24-AUC10, p=0.94, respectively). AR10-AUC30, but not PL24-AUC10 levels, was significantly lower in warfarin and NOACs groups at 3 days and 1 month after RFCA. Multiple logistic regression analysis identified AR10-AUC30 levels on the day of RFCA as a significant predictor of bleeding events in the period of three months after RFCA [odds ratio (OR) 20.6; 95% confidence interval (95%CI): 2.46 to 172.6; p=0.005]. Receiver-operating characteristic analysis showed that AR10-AUC30 levels on the day of RFCA significantly predicted bleeding events [AUC 0.849 (95%CI: 0.719-0.979; p&lt;0.001)]. The cut-off levels of AR10-AUC30 were 1647.6 for identification of bleeding events within three months after RFCA. These results suggested that AR10-AUC30 level determined by T-TAS is a potentially useful marker for assessment of the efficacy and safety of anti-coagulant therapy including warfarin and NOACs, in AF patients undergoing RFCA.

Disease dynamics in patients with acute myeloid leukemia: New biomarkers

Acute myeloid leukemia (AML) is characterized by rapid growth of leukemic blast cells. Extracellular vesicles (EVs), shedding from various cells, express antigens, reflecting their cellular origin. The current study was designed to explore the role of circulating EVs as potential biomarkers of AML activity and predictors of thrombogenicity in patients with this malignancy. Blood samples were collected from healthy controls and patients with newly diagnosed AML at three time points: diagnosis, nadir, and remission. EV concentration, cell origin, and expression of coagulation proteins were characterized using fluorescence-activated cell sorting. EV cytokine contents were evaluated by protein array. Procoagulant activity was assessed using Factor Xa chromogenic assay. Forty-two AML patients were enrolled in the study. Total EV numbers were higher in patients in first remission compared with controls, whereas blast EV counts were higher in patients at diagnosis compared with controls and patients in remission. Blast EV levels were significantly lower in patients who achieved remission and were alive at 3-year follow up compared with their succumbed counterparts. At all three time points, percentage of endothelial EVs was higher in patients compared with controls. EV procoagulant activity was elevated at diagnosis and in remission, and, unlike controls' EVs, patients' EVs increased endothelial cell thrombogenicity. EVs of AML patients express membrane proteins of blast cells and might serve as biomarkers of leukemia dynamics and presence of minimal residual disease. Increased levels of endothelial EVs and their procoagulant activity may indicate a vascular injury associated with a hypercoagulable state in AML.

A novel quantitative assessment of whole blood thrombogenicity in patients treated with a non-vitamin K oral anticoagulant

Non-vitamin K oral anticoagulants(NOAC) negate complex patient management issues, such as frequent blood sampling, diet restriction, and drug interactions, that had to be dealt with during the warfarinonly era. However, there is no definite tool tomonitor the anticoagulant effects of NOACs, although some patients suffer from bleeding complications related to exceedingly high blood concentrations of NOACs. [1, 2] Routine tests, such as prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), can be problematic formonitoring the anticoagulant effects of all NOACs because each individual NOAC has a different characteristic chemical structure and different pharmacokinetic profile (e.g., plasma half-life and tissue penetration rate) [3]. Recently, the Total Thrombus-formation Analysis System (T-TASTM) [4,5], a microchip-based flow chamber system capable of evaluating whole blood thrombogenicity, was developed as an easy-to-use system for quantitative analysis of thrombus formation (Fig. 1A,B). In the present study, we sought to examine whether the T-TASTM was useful for the quantitative analysis of thrombogenicity in patients treated with the NOAC edoxaban (Fig. 1C, D). We recruited 20 consecutive patients (male: n = 8 [40%] and female: n=12 [60%], average age: 75.2±8.7 years)whowere scheduled

Is There Attenuation of Benefit of Invasive Therapy in Patients with Chronic Kidney Disease? Results from Randomized Trials and Registry Data

Chronic kidney disease (CKD) is not only a common comorbidity among patients presenting with acute coronary syndrome (ACS), it is also an entity that portends worse short- and long-term prognosis. Differences in the pathophysiology of arterial atherosclerosis and calcification, chronic inflammation, platelet reactivity, and thrombogenicity in patients with and without CKD underpin the increased vulnerability of CKD patients with ACS to subsequent ischemic and bleeding complications. These differences, as well as the frequent exclusion of CKD patients from randomized control trials, create uncertainty regarding the benefit of invasive treatment for ACS in patients with CKD. The limited evidence from randomized trials suggests a benefit with invasive treatment in CKD patients with ACS. However, some data from registry studies suggest no benefit or even harm with invasive therapy. Thus, the optimal management of ACS in patients with CKD, in particular end-stage CKD, remains uncertain. In this article we review the characteristics of coronary artery disease in patients with CKD, the available evidence pertaining to the outcomes of CKD patients with ACS with invasive versus conservative therapy, and potential areas for reducing complications of invasive therapy in this high-risk subset of patients.

Plasma Tissue Factor Levels and Salivary Tissue Factor Activities of Periodontitis Patients with and without Cardiovascular Disease

The association between periodontal and cardiovascular disease has received considerable attention. Studies have demonstrated a higher incidence of atherosclerotic complications in patients with periodontal disease. Tissue factor (TF) has been known as a key initiator of the coagulation cascade, and the TF pathway is the primary physiological mechanism of initiation of blood coagulation. Recently, it has been shown that the circulating pool of TF in blood is associated with increased blood thrombogenicity in patients with coronary artery disease (CAD). Various tissues and saliva have been known to have TF activity. Consequently, the aim of this study was to investigate plasma TF levels and TF activity of saliva in periodontitis patients with and without diagnosed CAD. Twenty-six patients with a diagnosis of CAD and 26 systemically healthy patients were examined in the dental clinic, and the Community Periodontal Index Treatment Needs (CPITN) scores were recorded. Plasma TF levels were determined using commercially available ELISA kit. Salivary TF activities were determined according to Quick’s one-stage method. Plasma TF levels were significantly increased in patients with CAD when compared with the control group. There was no difference in salivary TF activities between the 2 groups, but there was a strong and negative correlation between salivary TF activities and CPITN indexes in both groups. In order to determine the possible role of TF activity as a salivary marker in CAD and periodontitis and to fully understand the negative correlation between salivary TF activities and CPITN, TF activity of gingival crevicular fluid that may also affect saliva can be evaluated.

Seasonal Variation in Thrombogenicity of Blood: A Word of Caution

Thrombogenicity of blood is known to have seasonal variations. The clinical implications of seasonal variations in the anticoagulation profile of patients with mechanical valves was assessed. Data of patients implanted with a mechanical heart valve for more than 3 months were collected at follow-up or on presentation to the emergency department. The mean time from the previous follow-up examination was 3.6 +/- 0.3 months. The number of patients with an international normalized ratio >3.5 and the incidence of hemorrhagic events peaked in hottest part of the year (June-July), with 128 cases of prolonged clotting and 43 hemorrhagic events in this period. The number of patients with rapid clotting and the incidence of embolic events peaked in coldest part of the year (December-January), with 120 cases of international normalized ratio <1.5 and 37 embolic events in this period. There was a significant correlation between temperature and thrombogenicity in patients with prosthetic heart valves on long-term anticoagulation.

Thrombogenicity in patients with percutaneous coronary artery intervention and dual antiplatelet treatment

Antiplatelet drugs are very effective and widely used for both the initial management of acute coronary syndrome and the long-term prevention of myocardial infarction, stroke, and peripheral artery disease. Dual antiplatelet therapy with clopidogrel and aspirin is more effective than aspirin monotherapy in most patients with cardiovascular disease.1,2 In addition, in patients with percutaneous coronary artery intervention (PCI), the addition of cilostazol on top of the dual antiplatelet treatment further increases clinical efficacy, as was shown in the CREST (Cilostazol for RESTenosis) trial.3 Finally, in a large randomized trial in 13 608 patients who were scheduled for PCI, prasugrel, a more potent and rapidly acting thienopyridine compound than clopidogrel, was more effective in reducing death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke.4 So, the degree of platelet function inhibition directly relates to clinical outcome in patients with PCI. Despite the use of more potent antiplatelet drugs, a considerable number of vascular patients have recurrent thrombotic events after PCI.5 It is thought that an ineffective response to these drugs contributes to the occurrence of these events, although the prevalence of aspirin resistance using aggregometry is only between 5.2 and 8%.6 The current literature is, … *Corresponding author. Tel: + 31205665976, Fax: + 31206968833, Email: p.w.kamphuisen{at}amc.uva.nl

The Risk of Intrauterine Growth Restriction (IGR) Is Increased by Risk Determinants of Arterial Thrombosis.

Background: As previously shown, the risk of cardiovascular disease is higher after a maternal placental syndrome, especially in the presence of fetal compromise. The HPA1-b allele of the ß3 subunit of the essential platelet integrin Alphallbbeta3 is a risk factor for increased platelet thrombogenicity, leading to arterial vascular occlusion also triggered by inflammatory endothelial alterations. We performed a case-control study to assess hereditary risk factor for arterial thrombosis in addition to the known risk determinants for venous thrombosis as risk determinants for fetal IGR.Materials and Methods: 121 women with severe fetal IGR (defined by birth weight below the 5th- percentile for gestational age and sex) and 300 normal women were evaluated. Women with other reasons of IGR (history of venous thrombosis, fetal loss, and preeclampsia, neonatale immunthrombocytopenia) were excluded. The fetuses were born alive after the 24th week of gestation.Results: A significant risk association could be shown for the HPA-1b/1b genotype OR 3.1 (95%CI 1.2–8.8), increased levels of lipoprotein (a) (>0.2g/l) OR 1.7 (95%CI 1.0–2.9), increased levels of fibrinogen (>median 284mg/dl) OR 2.8 (95%CI 1.8–4.4) increased levels of FVIII:C (>median 147%) OR 1.7 (95%CI 1.1–2.7), and increased levels of von-Willebrand-factor antigen (vWF-Ag) (>median 129%) OR 2.7 (95%CI 1.1–2.7). The combination of risk determinants led to a further increase in risk (e.g. HPA-1b allele, increased lipoprotein (a) and vWF-Ag OR 14.0) There was no significant risk association for factor V Leiden G1691A OR 1.3 (95% CI 0.7–2.81), and prothrombin G20210A mutation. OR 2.0 (95% CI 0.6–6.5)Conclusions: Increased platelet thrombogenicity via interaction with an inflammatory vascular process and/or via plasma levels of components of hemostasis/receptor ligands appear to be more important in women with IGR than the established risk determinants for venous thrombosis. Pharmacological control of the observed platelet thrombogenicity in patients at risk may be of clinical relevance. In consequence, it will be of importance to examine whether the critical subgroup of patients can benefit from prevention with specific antiplatelet agents.

Women with the Prothrombophilic HPA-1b Genotype of Platelet Integrin αIIbβ3 Are at Increased Risk of Intrauterine Growth Restriction.

Background: Disturbances in the placental vascular development with endothelial inflammation and thrombotic occlusion of the placental vasculature are associated with fetal intrauterine growth restriction (IGR). As shown in previous studies, the HPA-1b allele of the b subunit of the essential platelet integrin αIIbβ3, also known as glycoprotein IIb–IIIa, can be associated with increased platelet thrombogenicity, leading to arterial vascular occlusion also triggered by inflammatory endothelial alterations. We performed a case-control study to assess HPA-1b as risk determinant for fetal IGR.Materials and Methods: Fifty two women with fetal IGR (defined by birth weight below the 5th- and 10th percentile for gestational age and sex) were evaluated. Women with other reasons of IGR (history of venous thrombosis, fetal loss, and preeclampsia) were excluded. The fetuses were born alive after the 24th week of gestation. As control subjects, 307 normal women with at least one previous pregnancy and no previous pregnancy complication were included.Results: There was a significant risk association of the HPA-1b/1b genotype (birth weight below 5% percentile: odds ratio (OR) 6.3 (95% confidence interval (CI) 1.4–21); birth weight below 10% percentile: OR 4.6 (95% CI 1.4–15). OR for the HPA-1b/1b genotype (birth weight below 5% percentile) in subgroups with increased levels of fibrinogen (above median > 284mg/dl) were 17.7 (95% CI 2.9–106) and increased levels of FVIII:C (above median > 147%) were 22.1 (95% CI 3.8–127). No significant difference between the genotype distribution was found in patients with low levels of fibrinogen and/or FVIII:C. Similar results were found for women with IGR with a birth weight below the 10% percentile. There was no significant risk association for factor V Leiden G1691A, prothrombin G20210A mutation, and MTHFR 677TT.Conclusions: The platelet receptor genotype HPA-1b/1b is significantly associated with IGR. As possible pathological mechanism, an increased HPA-1b-associated thrombogenicity of platelets leading to IGR via interaction with an inflammatory vascular process and/or via increased levels of FVIII:C or plasma fibrinogen have to be considered. Pharmacological control of the observed platelet thrombogenicity in patients at risk may be of clinical relevance. In consequence, it will be of importance to examine whether this critical subgroup of patients can benefit from prevention with specific antiplatelet agents.