bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships between Haemostatic Factors and Capillary Morphology in Human Diabetic Neuropathy
Authors: Ford Isobel , Malik Rayaz A , Newrick Paul G , Preston F Eric , Ward John D , Greaves Michael 
Published: July 2018

SummaryWe have examined haemostatic factors in 15 diabetic patients with peripheral neuropathy and 10 diabetic patients without clinical complications. Plasma and blood viscosity, fibrinogen, factor VIIIc, von Willebrand factor activity, spontaneous platelet aggregation and fibrinolytic activity were not significantly different between diabetic patients without clinical complications and diabetic patients with peripheral neuropathy. Platelet aggregation was enhanced in diabetic patients with neuropathy compared with those without complications. In the 15 patients with neuropathy and 3 without complications, who underwent biopsy of sural nerve, skin and muscle, associations were found between haemostatic variables and measures of nerve capillary pathology, notably: plasma fibrinogen and nerve capillary basement membrane thickness (r = 0.70, p <0.001); thromboxane B2 production and nerve capillary basement membrane thickness (r = –0.61, p <0.01); plasma fibrinolytic activity and endoneurial capillary lumen size (r = 0.60, p <0.01) and endothelial cell outer perimeter (r = 0.65, p <0.01). The main associations of skin and muscle capillary abnormalities were with measures of in vitro platelet aggregation, and the correlations found with nerve capillary measurements were not echoed in the overlying muscle and skin. The results are supportive of the involvement of haemostatic abnormalities in the pathogenesis of diabetic neuropathy.
Tissue Factor Localization in Non-Human Primate Cerebral Tissue
Authors: del Zoppo Gregory J , Yu Jian-Qing , Copeland Brian R , Thomas Winston S , Schneiderman Jacob , Morrissey James H 
Published: July 2018

SummaryTissue factor (TF), the principal procoagulant of human brain, resides in specific regions of the non-human primate central nervous system. Immunohistochemical studies employing murine anti-human TF monoclonal antibodies (MoAbs) detected TF antigen in the cortex, basal ganglia, cerebellum, and cervical spinal cord in three normal baboon subjects. Although significantly less prominent than human cortical gray matter, a distinct partition of TF in gray matter >white matter was noted. The gray matter predilection of TF was confirmed in primate temporal and parietal lobe cortex by both sandwich ELISA and one-stage coagulation assay. Variation in the relative quantity of TF antigen was observed by ELISA among the three subjects studied. Procoagulant activity followed the pattern of TF antigen (cortical gray matter >basal ganglia ≥cerebellum >cortical white matter), and was 96.5–98.5% inhibitable by a function inhibiting anti-human TF MoAb combination. TF antigen was associated with the microvasculature of all cerebral tissues studied, and spared capillaries most selectively in the cerebral cortex, basal ganglia, and cerebellum. These findings suggest a highly specific ordering of TF antigen and related procoagulant activity in the central nervous system of the baboon, confined primarily to gray matter parenchyma, and to the non-capillary microvasculature.
Inhibition of Platelet Adhesion to Fibrin(ogen) in Flowing Whole Blood by Arg-Gly-Asp and Fibrinogen γ-Chain Carboxy Terminal Peptides
Authors: Hantgan Roy R , Endenburg Silvia C , Cavero I , Marguerie Gérard , Uzan André , Sixma Jan J , de Groot Philip G 
Published: July 2018

SummaryWe have employed synthetic peptides with sequences corresponding to the integrin receptor-recognition regions of fibrinogen as inhibitors of platelet aggregation and adhesion to fibrinogen-and fibrin-coated surfaces in flowing whole blood, using a rectangular perfusion chamber at wall shear rates of 300 s–1 and 1,300 s–1. D-RGDW caused substantial inhibition of platelet aggregation and adhesion to fibrinogen and fibrin at both shear rates, although it was least effective at blocking platelet adhesion to fibrin at 300 s–1. RGDS was a weaker inhibitor, and produced a biphasic dose-response curve; SDRG was inactive. HHLGGAK-QAGDV partially inhibited platelet aggregation and adhesion to fibrin(ogen) at both shear rates. These results support the identification of an RGD-specific receptor, most likely the platelet integrin glycoprotein IIb: III a, as the primary receptor responsible for platelet: fibrin(ogen) adhesive interactions under flow conditions, and indicate that platelet adhesion to surface bound fibrin(ogen) is stabilized by multivalent receptor-ligand contacts.
Protein S Tokushima: An Abnormal Protein S Found in a Japanese Family with Thrombosis
Authors: Shigekiyo T , Uno Y , Kawauchi S , Saito S , Hondo H , Nishioka J , Hayashi T , Suzuki K 
Published: July 2018

SummaryAn abnormal protein S (PS) was found in a Japanese family with a high incidence of thrombosis. The proband is a woman who was born in Tokushima Prefecture. She had superior sagittal sinus thrombosis, thrombophlebitis of the left leg, and thrombosis of the placenta. She had a normal plasma level of free PS antigen but decreased PS activity. Her mother and aunt also had thrombophlebitis of the leg, and together with four other family members also showed a normal level but decreased activity of PS. This suggests that hereditary dysfunction of PS is inherited in this family as an autosomal dominant trait. The proband’s PS appears to have a slightly higher molecular weight than normal PS both in the intact and modified form, suggesting that it has a molecular defect on the carboxyl-terminal side of the thrombin-sensitive site. This abnormal PS with apparently unique characteristics was named PS Tokushima.
Replacement Therapy with a Purified Protein C Concentrate during Initiation of Oral Anticoagulation in Severe Protein C Congenital Deficiency
Authors: De Stefano V , Mastrangelo S , Schwarz H P , Pola P , Flore R , Bizzi B , Leone G 
Published: July 2018

SummaryThe case of an adult patient with moderately severe protein C deficiency (antigen 16%, activity 12%) is reported. Both parents had protein C levels compatible with heterozygous deficiency. Unlike other reported cases of severe protein C deficiency in adults, the onset of thrombotic symptoms occurred at 1 month of age; however, a symptom-free period until age 17 followed. Replacement therapy with a monoclonal antibody purified protein C concentrate was carried out during the initiation of oral anticoagulation after a course of i.v. heparin for deep vein thrombosis. The administration of the concentrate allowed maintenance of protein C above 50% until a stable therapeutic anticoagulation level could be obtained. This was reached within a short time, thus allowing safe administration of a loading dose of warfarin. We conclude that this approach to the prevention of skin necrosis seems more rapid and safer than previous schedules of oral anticoagulation in protein C-deficient patients.
Positive Association Between Self-Reported Fatty Food Consumption and Factor VII Coagulant Activity, a Risk Factor for Coronary Heart Disease, in 4246 Middle-Aged Men
Authors: Connelly J B , Roderick P J , Cooper J A , Meade T W , Miller G J 
Published: July 2018

SummaryRaised levels of factor VII coagulant activity (VIIC) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIC. We explored this further in 4,246 men aged 45–69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month.In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIC was 7.8% of standard (95% CI 5.1–10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIC, serum cholesterol and BMI. Thus, the VIIC difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level.This study adds to the evidence that dietary fat intake influences VIIC and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.
Features of Thrombi and Diagnostic Accuracy of Impedance Plethysmography in Symptomatic and Asymptomatic Deep Vein Thrombosis
Authors: Agnelli Giancarlo , Cosmi Benilde , Radicchia Stefano , Veschi Franca , Boschetti Enrico , Lupattelli Luciano , Rinonapoli Emanuele , Nenci Giuseppe G 
Published: July 2018

SummaryImpedance plethysmography (IPG) has high sensitivity and specificity in patients with symptomatic deep vein thrombosis (DVT) while it fails to detect asymptomatic DVT. The aim of this study was to determine whether the features of thrombi such as location, size and occlusiveness could explain the different accuracy of IPG in symptomatic and asymptomatic DVT patients. One-hundred and seventeen consecutive outpatients with a clinical suspicion of DVT and 246 consecutive patients undergoing hip surgery were admitted to the study. In symptomatic patients IPG was performed on the day of referral, followed by venography, while in asymptomatic patients IPG was performed as a surveillance programme, followed by bilateral venography.A venography proved DVT was observed in 37% of the symptomatic patients and 34% of the asymptomatic limbs. A significantly higher proportion of proximal DVTs was found in symptomatic patients than in asymptomatic patients (78% vs 46%; p = 0.001). The mean Marder score, taken as an index of thrombus size, was significantly higher in symptomatic patients than in asymptomatic patients (19.0 vs 9.6; p = 0.0001). A significantly higher proportion of occlusive DVTs was observed in symptomatic than in asymptomatic patients (69% vs 36%; p = 0.001).We conclude that the unsatisfactory diagnostic accuracy of IPG in asymptomatic DVT is due to the high prevalence of distal, small and non occlusive thrombi. Such thrombi are unlikely to cause a critical obstruction of the venous outflow and therefore to produce a positive IPG.
Characterization of Monocyte-Associated Factor V
Authors: Kappelmayer Janos , Kunapuli Satya P , Wyshock Edward G , Colman Robert W 
Published: July 2018

SummaryWe demonstrate that in addition to possessing binding sites for intact factor V (FV), unstimulated peripheral blood monocytes also express activated factor V (FVa) on their surfaces. FVa was identified on the monocyte surface by monoclonal antibody B38 recognizing FVa light chain and by human oligoclonal antibodies H1 (to FVa light chain) and H2 (to FVa heavy chain) using immunofluorescence microscopy and flow cytometry. On Western blots, partially cleaved FV could be identified as a 220 kDa band in lysates of monocytes. In addition to surface expression of FVa, monocytes also contain intracellular FV as detected only after permeabilization by Triton X-100 by monoclonal antibody B10 directed specifically to the Cl domain not present in FVa. We sought to determine whether the presence of FV in peripheral blood monocytes is a result of de novo synthesis.Using in situ hybridization, no FV mRNA could be detected in monocytes, while in parallel control studies, factor V mRNA was detectable in Hep G2 cells and CD18 mRNA in monocytes. In addition, using reverse transcriptase and the polymerase chain reaction, no FV mRNA was detected in mononuclear cells or in U937 cells, but mRNA for factor V was present in Hep G2 cells using the same techniques. These data suggest that FV is present in human monocytes, presumably acquired by binding of plasma FV, and that the presence of this critical coagulation factor is not due to de novo synthesis.
Protein C Activity in Healthy Volunteers - Influence of Age, Sex, Smoking and Oral Contraceptives
Authors: Tait R C , Walker Isobel D , Islam S I A M , McCall Frances , Conkie J A , Wight M , Mitchell R , Davidson J F 
Published: July 2018

SummaryInterpretation of protein C (PC) levels in a given individual has several limitations. A normal PC activity does not necessarily exclude a genetic deficiency nor can a reduced level confirm it. Measuring PC amidolytic activity in 9,648 healthy blood donors has allowed identification of demographic factors which cause variation in PC activity and further hinder interpretation. PC activity displays a log normal distribution and significant variation with age. This is most marked in young adult males when mean PC activity rises from 0.86 iu/ml (15–19 years) to 1.04 iu/ml (45–49 years; P <0.0001). Pre-menopausal females, who for most age ranges, have mean PC activity below their male contemporaries, show a less marked rise with age until the menopause when PC activity rises further. The use of hormonal contraceptive preparations is associated with an increase in mean PC activity of 0.05–0.08 iu/ml while smoking habit has no influence on PC activity.In view of these findings we strongly recommend the use of age and sex restricted reference ranges when interpreting PC activity.
Thrombolytic and Haemorrhagic Effects of Bolus Doses of Tissue-Type Plasminogen Activator and a Hybrid Plasminogen Activator with Prolonged Plasma Half-Life (K2tu-PA: CGP 42935)
Authors: Agnelli Giancarlo , Pascucci Claudia , Nenci Giuseppe G , Mele Antonio , Bürgi Rolf , Heim Jutta 
Published: July 2018

SummaryK2tu-PA is a hybrid plasminogen activator linking the kringle 2 domain of tissue-type plasminogen activator (t-PA) to the catalytic protease domain of single-chain urokinase-type plasminogen activator (scu-PA). K2tu-PA, as t-PA has high affinity for fibrin and is activated by fibrin but has a longer plasma half-life (over 30 min). The aim of this study was to compare the effects of bolus doses of recombinant t-PA (rt-PA) and K2tu-PA, on: 1) lysis of preformed thrombi (fibrinolysis), 2) accretion of new fibrin on pre-existing thrombi during fibrinolysis (thrombus growth), 3) thrombolysis as assessed by reduction of thrombus weight and 4) systemic plasma proteolysis and blood loss from a standard wound. A jugular vein thrombosis model and an ear bleeding model were adopted in rabbits. Saline produced 11 ± 2% fibrinolysis. rt-PA, 0.2 mg/kg, 0.4 mg and 0.8 mg/kg produced 35 ± 4%, 54 ± 4% and 78 ± 6% fibrinolysis, respectively. K2tu-PA, at the same doses, produced 39 ± 5%, 57 ± 6% and 83 ± 6% fibrinolysis, respectively. Thus, no differences in the fibrinolytic activity of rt-PA and K2tu-PA were observed. Injection of saline was followed by an accretion of 56.4 ± 5.9 μg of radioactive new fibrin on the thrombi. The injection of the three increasing doses of rt-PA was followed by an accretion of 54.9 ± 5.3 μg, 49.1 ± 6.1 μg and 47.2 ± 4.8 μg. The injection of three increasing doses of K2tu-PA was followed by an accretion of 38.1 ± 3.4 μg, 29.6 ± 2.5 μg and 17.1 ± 3.4 μg. At each of the three doses, K2tu-PA was more effective than rt-PA in reducing the accretion of new fibrin on the thrombi (p <0.01) and, as a consequence, in reducing thrombus weight (p <0.01). The two lower doses of rt-PA and K2tu-PA did not produce systemic proteolysis and bleeding. The highest dose of K2tu-PA produced a statistically significant more intense systemic proteolysis and bleeding than the highest dose of rt-PA.This study demonstrates that bolus doses of K2tu-PA and rt-PA produce a similar degree of fibrinolysis. Due to its longer half-life K2tu-PA is more efficient than rt-PA in inhibiting accretion of new fibrin on the thrombi during thrombolysis so that the thrombus size is more efficiently reduced. As a consequence the concomitant use of heparin might not be necessary. The potential increased risk of bleeding with bolus of high doses of K2tu-PA has to be seen in view of the advantage of avoiding the concomitant use of heparin.
The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis
Authors: Robbie Linda A , Booth Nuala A , Croll Alison M , Bennett Bruce 
Published: July 2018

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.
A Slow Clearing, Fibrin-Specific, PAI-1 Resistant Variant of t-PA (T103N, KHRR 296-299 AAAA)
Authors: Paoni Nicholas F , Keyt Bruce A , Refino Canio J , Chow Alice M , Nguyen Hung V , Berleau Lea T , Badillo Julie , Peña Luis C , Brady Kevin , Wurm Florian M , Ogez John , Bennett William F 
Published: July 2018

SummarySite directed mutagenesis was used to construct a t-PA variant that contains an additional glycosylation site in the first kringle domain (T103N) combined with a tetra-alanine substitution in the protease domain (KHRR 296-299 AAAA). This combination variant has a plasma clearance rate that is 4.5-fold slower in rats and 5.4-fold slower in rabbits than t-PA. It is also less than one tenth as active as t-PA towards plasminogen in the presence of fibrinogen, and has approximately twice the normal activity in the presence of fibrin. It shows substantial resistance to the fast acting inhibitor, plasminogen activator inhibitor-1 (PAI-1), requiring a 10-fold greater molar excess of PAI-1 to reduce its activity by 50%, compared to t-PA. This is the result of a reduction of nearly 100-fold in the second order rate constant for PAI-1 inactivation. These results show that it is possible to combine mutations in different domains of t-PA to construct a variant which is simultaneously slower clearing, less reactive towards plasminogen in the absence of a fibrin clot, and resistant to inactivation by PAI-1.
Functional Properties of p-Anisoylated Plasmin-Staphylokinase Complex
Authors: Lijnen H R , Van Hoef B , Smith R A G , Collen D 
Published: July 2018

SummaryThe kinetic and fibrinolytic properties of a reversibly acylated stoichiometric complex between human plasmin and recombinant staphylokinase (plasmin-STAR complex) were evaluated. The acylation rate constant of plasmin-STAR by p-amidinophenyl-p’-anisate-HCI was 52 M-1 s-1 and its deacylation rate constant 1.2 × 10-4 s-1 (t½ of 95 min) which are respectively 50-fold and around 3-fold lower than for the plasmin-streptokinase complex. The acylated complex was stable as evidenced by binding to lysine-Sepharose. However, following an initial short lag phase, the acylated plasmin-STAR complex activated plasminogen at a similar rate as the unblocked complex, whereas the acylated plasmin-streptokinase complex did not activate plasminogen. These findings indicate that STAR, unlike streptokinase, dissociates from its acylated complex with plasmin in the presence of excess plasminogen. In agreement with this hypothesis, the time course of the lysis of a 125I-fibrin labeled plasma clot submerged in citrated human plasma, is similar for acylated plasmin-STAR, unblocked plasmin-STAR and free STAR (50% clot lysis in 2 h requires 12 nM of each agent). The plasma clearances of STAR-related antigen following bolus injection in hamsters were 1.0 to 1.5 ml/min for acylated plasmin-STAR, unblocked plasmin-STAR and free STAR, as a result of short initial half-lives of 2.0 to 2.5 min.The dissociation of the anisoylated plasmin-STAR complex and its consequent rapid clearance suggest that it has no apparent advantages as compared to free STAR for clinical thrombolysis.
Effect of Diltiazem and Low-Dose Aspirin on Platelet Aggregation and ATP Release Induced by Paired Agonists
Authors: Zucker Marjorie L , Budd Susan E , Dollar Lawrence E , Chernoff Steven B , Altman Raul 
Published: July 2018

SummaryThe authors studied the effects of diltiazem, administered alone and together with low-dose aspirin, on the platelet response to paired agonists. After a baseline period, 25 healthy volunteers were given oral diltiazem for 1 week (120, 240, or 360 mg/day), and then crossed over randomly between 1 week on diltiazem plus aspirin (81 mg/day), and 1 week on aspirin (81 mg/day) alone. Platelet function was tested on 2 consecutive days in each period. Synergistic platelet aggregation and ATP release were obtained at baseline using a subthreshold concentration of arachidonic acid combined with platelet activating factor, ADP, or epinephrine. Diltiazem resulted in a significant decrease from baseline in platelet aggregation and ATP release using the arachidonic acid-epinephrine combination (35% and 40% decrease, respectively, p <0.01) and a significant decrease in aggregation using the arachidonic acid-ADP combination (22% decrease, p <0.01). The effects were neither dose-related, nor accompanied by any significant change in serum thromboxane B2 levels or bleeding times. There was no significant difference between the effects of aspirin alone and aspirin plus diltiazem on the synergistic platelet aggregation and ATP release induced by the paired agonists, or on thromboxane B2 levels or bleeding times. Diltiazem administered in vivo partially inhibits the synergistic platelet aggregation and ATP release induced by paired agonists; however, in contrast to a previous in vitro study it does not potentiate the platelet-inhibitory effect of aspirin.