bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Platelet Storage Organelles A Review
Authors: Fukami Miriam H. , Salganicoff Leon 
Published: July 2018

SummaryPlatelets contain numerous electron-dense subcellular organelles which have been referred to in the literature by various names such as α-granules, electron-dense and very electrondense granules, lysosomes, dense bodies, etc. Most of the organelles are secretory granules, since induction of secretion by appropriate stimuli causes degranulation of platelets and the appearance of the granule contents in the extracellular medium. Among the substances that are known to be stored and secreted by platelets are: serotonin, ATP, ADP, calcium, pyrophosphate, acid hydrolases, fibrinogen, vascular permeability factor, β-thromboglobulin, platelet factor 4 and growth factor.The recent literature concerning the localization of the secreted substances within specific platelet organelles is reviewed here. Results from electron microscopy and microprobe analysis, selective secretion experiments, subcellular fractionation studies and studies on platelets from patients with storage pool deficiency indicate that there are as many as four types of storage organelles in human platelets.
Prostaglandin Endoperoxide – Thromboxane Synthesis and Dense Granule Secretion as Positive Feedback Loops in the Propagation of Platelet Responses during “The Basic Platelet Reaction”
Authors: Holmsen Holm 
Published: July 2018

SummaryPlatelets respond to a great variety of stimuli by a sequential display of shape change, aggregation, prostaglandin/thromboxane synthesis – dense granule secretion and α-granule secretion. It is suggested that these responses are independent of each other, and caused by an increase in the concentration of a second messenger, liberated to the cytoplasm through the interaction between an extracellular agonist and the platelet membrane. The extent of the propagation of responses is determined by the strength of the stimulus. Stimuli can be subdivided into 1) original, applied stimuli and 2) platelet-produced stimuli (substances secreted from dense granules, prostaglandins and thromboxanes); these stimuli may act synergistically. In this way the platelet has two apparently independent means of potentiating their response to external stimuli which act as two separate positive feedback loops.
Effects of Sodium Azide on Platelet Function
Authors: Stibbe Jeanne , Holmsen Holm 
Published: July 2018

SummarySodium azide in low concentrations (0.1-10 μM) was found to have inhibitory effects on human platelet function. Primary aggregation induced by ADP, epinephrine, thrombin and the ionophore A 23187 was decreased. To evaluate the effect of azide apart from secondary processes, the platelets were treated with indomethacin to prevent prostaglandin/thromboxane synthesis for all inducers; in addition, effects of secreted ADP, in the case of thrombin and A 23187, was prevented by the presence of creatine phosphate plus creatine phosphokinase. ADP, epinephrine and A 23187, but not thrombin-induced primary aggregates, dispersed immediately upon addition of azide. Azide powerfully inhibited dense granule secretion induced by collagen, ADP and epinephrine as measured both by 14C-serotonin secretion and as judged by secondary aggregation. Shape change induced by ADP, thrombin or A 23187 was not affected. Azide had no effect on energy metabolism. Since the aggregation experiments were performed in the presence of indomethacin, and malondialdehyde formation from arachidonic acid was not affected by azide, it seemed unlikely that the inhibition by azide of platelet function was related to inhibition of synthesis of prostaglandins and thromboxanes. It is concluded that azide exerts its effects directly on the common pathway for platelet responses.Abbreviations used: AA: arachidonic acid; PG-TX: PGG2, PGH2 and thromboxane A2; ETYA: 5, 8, 11, 14-eicosa-tetraynoic acid; MDA: malondialdehyde; PGE1 prostaglandin E1; db-c-GMP: dibutyryl 3’, 5’-cyclic guanosine monophosphate; ADP: adenosine diphosphate; c-AMP: 3’, 5’-cyclic adenosine monophosphate; CP: creatine phosphate; CPK: creatine phosphokinase; PRP: píatelet-rich plasma; PPP: platelet-poor plasma; GFP: gel filtered platelets.
The Role of Platelets in the Pathogenesis of Thrombosis and Hemorrhage in Patients with Thrombocytosis
Authors: Walsh Peter N. , Murphy Scott , Barry William E. 
Published: July 2018

SummarySome patients with thrombocytosis due to myeloproliferative diseases or other etiologies experience thromboembolic complications and others may bleed excessively. It seems unlikely that elevations in platelet count per se are a direct cause either of thrombosis or of hemorrhage. In an effort to ascertain whether variations in platelet function might determine whether an individual patient experiences thrombotic or hemorrhagic complications we have evaluated platelet function in 22patients with thrombocytosis due to a variety of etiologies. The results of platelet counts, bleeding time determinations, and studies of platelet aggregation were similar in patients with thrombosis, in patients with bleeding and in patients with neither complication. Therefore, detailed studies of platelet coagulant activities were carried out in 8patients. The results of platelet coagulant activity assays were normal in all 3patients with thrombocytosis and neither thrombotic nor bleeding complications and an additional 3patients with myeloproliferative diseases, normal platelet counts and no thrombohemorrhagic complications. In 2patients with thrombotic complications significant elevation of platelet coagulant activities concerned with the early phases of intrinsic coagulation were observed whereas in 2patients with severe hemorrhagic complications deficiences of either contact forming activity or collagen-induced coagulant activities were evident. This preliminary study suggests the possibility that variations in platelet coagulant activities concerned with the early stages of intrinsic coagulation may determine whether patients with thrombocytosis will experience bleeding or thrombotic complications.
Early Activation of Hemostasis during Cardiopulmonary Bypass: Evidence for Thrombin Mediated Hyperfibrinolysis
Authors: Teufelsbauer H , Proidl Sylvia , Havel M , Vukovich Th 
Published: July 2018

SummaryIn 14 consecutive patients undergoing cardiopulmonary bypass for coronary bypass surgery the time course of coagulation and fibrinolysis markers were measured, e.g. plasma levels of thrombin-antithrombin III (TAT) complexes, cross-linked fibrin degradation products (X1FDP) and plasmin-α2-antiplasmin complexes (PAP). TAT levels exceeded the 90% baseline percentile already during CPB (after opening of aortic clamp) in 10 patients, whereas PAP and X1FDP exceeded their 90% percentile in only one patient at this time. Concerning fibrinolysis markers PAP and X1FDP the majority of patients showed elevations higher than their 90% baseline percentile only 1 h postoperation. Correlation analysis revealed significant dependencies between TAT levels during and at the end of CPB and PAP levels 1 h postoperation (R = 0.55 and R = 0.56 respectively). Furthermore, 1 h postoperation X1FDP levels were significantly correlated with both TAT and PAP. Peak X1FDP levels at the same time correlated with blood loss via thoracic drains (R = 0.56). Thus, we suggest that hyperfibrinolysis in patients undergoing CPB is at least partly due to hypercoagulation. Clinically, this may implicate that intensified anticoagulation could prevent hyperfibrinolysis and reduce postoperative blood loss.
Detection of Asymptomatic Deep Vein Thrombosis by Real-Time B-Mode Ultrasonography in Hip Surgery Patients
Authors: Agnelli Giancarlo , Volpato Raul , Radicchia Stefano , Veschi Franca , Di Filippo Paolo , Lupattelli Luciano , Nenci Giuseppe G 
Published: July 2018

SummaryThe aim of this study was to prospectively evaluate the accuracy of real-time B-mode ultrasonography in the diagnosis of asymptomatic proximal deep vein thrombosis (DVT) in hip surgery patients. Venography was adopted as the gold standard. We studied 100 consecutive patients undergoing hip surgery: 60 patients for hip fracture and 40 patients for elective hip replacement. Bilateral real-time B-mode ultrasonography was performed prior to bilateral venography. The two diagnostic procedures were performed on the same day by different investigators unaware of the assigned prophylatic regimen for DVT Compressibility of the vein segment was adopted as the single criterion for DVT. Venography was performed and judged by radiologists unaware of the ultrasonography results. In 13 limbs venography was either impossible to perform or not adequate for judgement. Ultrasonography and an adequate venography was obtained in 187 limbs. A venography proven DVT was observed in 49 limbs (26.2%) and a proximal DVT in 21 limbs (11.2%). All the patients were asymptomatic for DVT. The sensitivity and specificity of real time B-mode ultrasonography for proximal DVT were 57% (95% confidence interval: C. I. 36–80) and 99% (C. I. 99–100), respectively and the positive and negative predictive values were 93% (C.I. 73–100) and 95% (C.I. 91–97), respectively. The sensitivity and specificity for overall DVT were 25% (C.I. 11–38) and 99% (C.I. 97–100), respectively and the positive and negative predictive values were 92% (C. I. 73–100) and 79% (C.I. 76–85), respectively. Our data indicate that realtime B-mode ultrasonography for its high specificity could make venography unnecessary in patients with positive results. However, because of its low sensitivity it cannot be used for the screening of DVT in asymptomatic patients, nor can it replace venography for outcome measurements in clinical trials on DVT prophylaxis.
A Six Year Prospective Study of Fibrinogen and Other Risk Factors Associated with Mortality in Stable Claudicants
Authors: Banerjee A K , Pearson J , Gilliland E L , Goss D , Lewis J D , Stirling Y , Meade T W 
Published: July 2018

SummaryA total of 333 patients with stable intermittent claudication at recruitment were followed up for 6 years to determine risk factors associated with subsequent mortality. Cardiovascular diseases were the underlying cause of death in 78% of the 114 patients who died. The strongest independent predictor of death during the follow-up period was the plasma fibrinogen level, an increase of 1 g/l being associated with a nearly two-fold increase in the probability of death within the next 6 years. Age, low ankle/brachial pressure index and a past history of myocardial infarction also increased the probability of death during the study period. The plasma fibrinogen level is a valuable index of those patients with stable intermittent claudication at high risk of early mortality. The results also provide further evidence for the involvement of fibrinogen in the pathogenesis of arterial disease.
Antiphospholipid Antibody Positive Sera Enhance Endothelial Cell Procoagulant Activity – Studies in a Thrombosis Model
Authors: Oosting Janine D , Derksen Ronald H W M , Blokzijl Laya , Sixma Jan J , de Groot Philip G 
Published: July 2018

SummaryThe effect of sera and IgG from 12 patients with systemic lupus erythematosus (SLE) on the endothelial cell (EC) procoagulant activity (PCA) was investigated in an in vitro thrombosis model. Six of the 12 SLE sera contained antiphospholipid antibodies (aPL).EC were stimulated for 8 h at 37° C with or without 50 pM tumor necrosis factor (TNF) in culture medium containing 20% patient or control serum. Then the endothelial cell matrix (ECM) was isolated and subsequently exposed in a perfusion chamber to circulating normal whole blood, anticoagulated with low molecular weight heparin (LMWH). The PCA of the ECM was determined as the amount of generated fibrinopeptide A (FPA) in samples taken before and after perfusion. Furthermore, cross sections were made of the perfused matrix and analyzed for platelet adhesion and aggregate formation.All six aPL containing sera induced a small, but significant increase of ECM procoagulant activity. When added in combination with a low dose of TNF (50 pM), a synergistic enhancement of ECM procoagulant activity was found. The FPA generation was increased to 150–614% from the values obtained after stimulation with TNF and control serum. Also a shift towards the formation of larger platelet thrombi was observed. After stimulation with TNF and patient serum the surface of ECM covered with large aggregates (> 5 µm) was increased by 124–329% compared to the results obtained after stimulation with control serum and TNF. When patient sera were depleted from IgG the effects were strongly decreased.These data show that the potentiation of TNF-induced PCA formation by aPL containing sera from patients with SLE leads to enhanced thrombus formation in an in vitro thrombosis model. This may help explain the increased thrombotic tendency in these patients.
The Prevalence of Factor XII Deficiency in 103 Orally Anticoagulated Outpatients Suffering from Recurrent Venous and/or Arterial Thromboembolism
Authors: Halbmayer Walter-Michael , Mannhalter Christine , Feichtinger Christine , Rubi Karl , Fischer Michael 
Published: July 2018

SummaryOne hundred and three patients suffering from recurrent venous thrombosis, recurrent arterial thromboembolism and/or recurrent myocardial infarction and 50 healthy subjects were tested for Hageman factor (FXII) coagulant activity and antigen. Among the 103 patients we identified 15 subjects with FXII deficiency (15%), 3 with protein C deficiency (3%) and 3 with protein S deficiency (3%). Combined FXII and protein C, protein S or antithrombin III deficiency was not observed. The 103 patients were devided into subgroups according to the type of thrombotic complication. Among patients with exclusively recurrent venous thromboembolism 8% (p = 0.153) were deficient in FXII. Among patients suffering from recurrent arterial thromboembolism and/or myocardial infarction, the incidence of FXII deficiency was significantly higher (20%, p < 0.003). In 67% of the patients with FXII deficiency a positive family history of thrombosis could be established. In contrast, only 32% of all venous and 28% of all arterial thrombosis patients had a positive family history. We believe that reduced levels of FXII should be considered as a risk factor in the development of thromboembolism. Consequently, more attention should be payed to the measurement of FXII when evaluating thromboembolic risk factors especially in cases of recurrent arterial thromboembolism and/or myocardial infarction.
Effect of Tissue Factor Pathway Inhibitor (TFPI) in the HEPTEST® Assay and in an Amidolytic Anti Factor Xa Assay for LMW Heparin
Authors: Kristensen Hanne I , Østergaard Per B , Nordfang Ole , Abildgaard Ulrich , Lindahl Anne Karin 
Published: July 2018

SummaryBoth the HEPTEST® and amidolytic anti factor Xa assays are currently being used for heparin activity detection in plasma from patients receiving standard heparin or low molecular weight heparin (LMWH). In this study we have investigated the influence of recombinant and endogenous Tissue Factor Pathway Inhibitor (TFPI) on these assays. The HEPTEST® determinations were performed on an ACL 300 R Clottimer using the APTT program which resulted in a longer incubation time with factor Xa than recommended by the manufacturer. rTFPI added to plasma prolonged the HEPTEST® clotting time markedly, but had only a little effect in the amidolytic assay. Antibodies against TFPI (anti-TFPI) abolished these effects. The effect of adding rTFPI and Logiparin® was additive. When anti-TFPI IgG was added to samples of normal plasma, a statistically significant shortening of the HEPTEST® clotting time was seen. When anti-TFPI was added to plasma samples from volunteers who had received Logiparin® by subcutaneous or intravenous injection, then the HEPTEST® clotting time was shortened considerably. For some samples the clotting time was halved. These experiments show that the HEPTEST® clotting time is prolonged not only by heparin-antithrombin III, but also by TFPI released by heparin injection.
Fibrin Clot Lysis by Thrombolytic Agents Is Impaired in Newborns due to a Low Plasminogen Concentration
Authors: Andrew M , Brooker L , Leaker M , Paes B , Weitz J 
Published: July 2018

SummaryAlthough thrombolytic drugs have been extensively used in adults, there is sparse information on their effectiveness in newborns whose fibrinolytic system differs significantly from adults. The purpose of this study was to determine if low plasma levels of plasminogen in cord plasma limited the therapeutic effectiveness of thrombolytic agents. Urokinase (UK), streptokinase (SK) and tissue plasminogen activator (TPA) were compared for their ability to lyse washed 125I-labelled adult or cord fibrin clots suspended in cord or adult plasma. 125I-labelled fibrin clots were prepared by recalcifying cord or adult plasma spiked with labelled fibrinogen and then placed into cord or adult plasma which contained either saline or differing amounts of a specific thrombolytic agent. After a 60 min incubation, the remaining 125I-fibrin in clots released 125I-fibrin fragments, and concentrations of fibrinogen, α2-antiplasmin, and plasminogen in the bathing plasma were measured and compared to starting values. Cord fibrin clots were more resistant than adult fibrin clots to all thrombolytic drugs tested (p <0.001). On average, the cord system retained 27% more 125I-fibrin in clots, and released 32% less 125I-fibrin fragments into plasma. Fibrinogenolysis was also decreased in cord plasmas compared to adult plasmas. The degree of fibrinolysis and fibrinogenolysis in cord plasma increased to adult values when plasminogen concentrations were increased in the bathing plasma. Thus, cord fibrin clots have an impaired response to thrombolytic agents secondary to low levels of plasminogen. We speculate that the clinical response of newborns to thrombolytic agents is also impaired and will not be enhanced by increasing doses of thrombolytic agents but may be enhanced by increasing the concentration of plasminogen.
Synergistic Antithrombotic Properties of G4120, a RGD-Containing Synthetic Peptide, and Argatroban, a Synthetic Thrombin Inhibitor, in a Hamster Femoral Vein Platelet-Rich Thrombosis Model
Authors: Imura Yoshimi , Stassen Jean-Marie , Vreys Ingrid , Lesaffre Emmanuel , Gold Herman K , Collen Désiré 
Published: July 2018

SummaryThe synergistic antithrombotic properties of G4120, a synthetic Arg-Gly-Asp (RGD) containing peptide which strongly inhibits platelet aggregation, and of Argatroban, a synthetic thrombin inhibitor, were examined in a reproducible quantitative hamster femoral vein platelet-rich mural thrombosis model. Bolus injections of G4120 and Argatroban inhibit thrombus formation in a dose-dependent way; 50% inhibition (ID50) is obtained with 11 µg/kg G4120 and with 2 mg/kg Argatroban. Combined bolus injections of 3 µg/kg G4120 with 0.5, 0.75 or 1 mg/kg Argatroban and of 1 mg/kg Argatroban with 1.5 or 3 µg/kg G4120 caused linear dose-dependent inhibition of thrombus formation, whereas 3 µg/kg G4120 or 1 mg/kg Argatroban alone had very little effect (<20% inhibition). ID50 was obtained with the combination of 3 µg/kg G4120 and 0.5 mg/kg Argatroban, corresponding to an equi-effective fractional combination of 0.62 with a 95% confidence interval of 0.50 to 0.74. Alternatively the ID50 was obtained with the combination of 1 mg/kg Argatroban and 1.3 µg/kg G4120, corresponding to an equi-effective fractional combination of 0.52 with a 95% confidence interval of 0.18 to 0.86. In both instances these results are indicative of a significant synergistic interaction. Bolus injection of 10 mg/kg aspirin, 100 U/kg heparin or the combination did not inhibit thrombus formation.The synergistic effect of the combination of platelet inhibiting RGD-peptides and synthetic thrombin inhibitors could be useful in the prevention of arterial occlusion with platelet-rich thrombus in patients with ischemic heart disease following thrombolytic therapy or angioplasty, although this combination is not expected to reverse platelet thrombus formation.
Low Molecular Weight Fibrinogen Degradation Products Stimulate the Release of Growth Factors from Endothelial Cells
Authors: Lorenzet Roberto , Sobel Joan H , Bini Alessandra , Witte Larry D 
Published: July 2018

SummaryCultured porcine aortic endothelial cells (PAEC) constitutively produce and secrete in their culture medium mitogens collectively called endothelial cell-derived growth factors (EDGFs). Incubation of PAEC with fibrinogen-degradation products (FDPs) obtained by plasmin digestion of highly purified fibrinogen caused an increased release of EDGFs, as assessed by [3H]-thymidine incorporation in 3T3 mouse fibroblasts. The effect was time-dependent and correlated with the degree of fibrinogenolysis. It was accompanied by elongation of the cells. Neither increase in EDGFs release nor cell damage was observed when non-degraded fibrinogen was incubated with endothelial cells. Low molecular weight fibrinogen degradation products (LMWFDPs) (M
r ≤ 10,000), and the higher molecular weight fibrinogen fragments D and E were tested under the same conditions. Only the LMWFDPs caused elongation and damage to PAEC and a marked stimulation (up to 12 fold) of EDGFs release. A low density growth assay revealed that the released EDGFs were mitogenically active on the same PAEC. The activity of the released EDGFs was time and dose dependent on both 3T3 fibroblasts and PAEC, indicating that LMWFDPs caused enhanced release of EDGFs that can act in paracrine and autocrine fashion. This study suggests an additional role for fibrinogenolysis contributing to wound healing, and possibly to atherosclerosis.
No Association between Thrombin Generation and Intra-Plaque Haemorrhage in Symptomatic Carotid Atherosclerotic Plaques: The Plaque at RISK (PARISK) Study
Authors: Crombag Geneviève , Spronk Henri , Nelemans Patty , Schreuder Floris , Truijman Martine , van Dijk Anouk , de Rotte Alexandra , Liem Madieke , Daemen Mat , van der Steen Anton , Mess Werner , Nederkoorn Paul , Hendrikse Jeroen , van der Lugt Aad , Wildberger Joachim , ten Cate Hugo , van Oostenbrugge Robert , Kooi M. 
Published: July 2018

Background Carotid atherosclerosis is an important cause of stroke. Intra-plaque haemorrhage (IPH) on magnetic resonance imaging (MRI) increases stroke risk. Development of IPH is only partly understood. Thrombin is an essential enzyme in haemostasis. Experimental animal studies have shown conflicting results on the relation between thrombin and plaque vulnerability. We hypothesize that decreased thrombin generation (TG) is associated with IPH and plaque vulnerability.
Objective This article investigates whether TG is associated with IPH and other features of plaque vulnerability in stroke patients.
Methods Recently symptomatic stroke patients underwent carotid MRI and blood sampling. MRI plaque features include plaque burden, presence of IPH, amount of lipid-rich necrotic core (LRNC), calcified tissue and fibrous tissue (% of total wall volume). TG was assessed in platelet-poor plasma and expressed as: peak height (PH) and endogenous thrombin potential (ETP). MR images could be analysed in 224 patients. Blood samples were available in 161 of 224 patients. Binary multivariate logistic and linear regression were used to investigate the association between TG and MRI plaque features.
Results IPH and LRNC were present in 65 (40%) and 102 (63%) of plaques. There were no significant associations between TG and IPH; PH odds ratio (OR) = 1, 95% confidence interval (CI): 0.76 to 1.45 and ETP OR = 1, 95% CI: 0.73 to 1.37. After correction for age, sex and hypercholesterolaemia, the association was weak but non-significant; PH: OR = 0.76, 95% CI: 0.52 to 1.10 and ETP: OR = 0.73, 95% CI: 0.53 to 1.37.
Conclusion Features of carotid plaque on MRI show no significant association with TG in stroke patients. Systemic TG does not seem to be an important factor in IPH development.