bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Cyclooxygenase-1 Genotype on ex vivo Aspirin Response in Patients at Risk for Stroke
Authors: Momary Kathryn M. , Shapiro Nancy L. , Brace Larry D. , Shord Stacy S. , Grossi Enzo , Viana Marlos A. , Helgason Cathy M. , Nutescu Edith A. , Cavallari Larisa H.
Published: April 2009

Background: We sought to determine whether cyclooxygenase-1 (PTGS1) genotype is associated with the ability of aspirin to inhibit platelet aggregation in patients at risk for stroke. Methods: Blood and urine samples were collected from 60 subjects, including 28 African Americans, who were taking aspirin for primary or secondary stroke prevention. Samples were analyzed for the PTGS1 A–707G, PTGS1 P17L, and glycoprotein IIIa (ITGB3)P1A1/A2 genotypes, ex-vivo platelet aggregation, serum cholesterol, plasma salicylate levels, and urinary 11-dehydrothromboxane B2 (11-dhTxB2) concentrations. The association between PTGS1 A–707G and P17L genotypes and aspirin response, as assessed by ex vivo studies and 11-dhTxB2 concentrations, was evaluated by statistical testing and nonlinear mapping. Results: Salicylate concentrations, ITGB3 genotype distribution and 11-dhTxB2 concentrations were similar among PTGS1 genotype groups. More subjects with the PTGS1 17PP versus PL genotype had incomplete ex-vivo inhibition of platelet aggregation by aspirin (57 vs. 20%; p = 0.04). Fifty-nine percent of subjects homozygous for both the PTGS –707A and 17P alleles, but none with both the PTGS1 –707G and 17L alleles had incomplete inhibition with aspirin; p = 0.04. Similarly, nonlinear mapping showed a direct relationship between the PTGS1 17P allele and decreased aspirin response. When analyzed separately by ethnicity, the association with the P17L genotype and aspirin response persisted in African Americans, but not Caucasians. Conclusions: Our data suggest that the PTGS1 P17L genotype contributes to response to aspirin as assessed by ex-vivo platelet aggregation. Our data further suggest that the association between PTGS1 genotype and aspirin response might vary by ethnicity.
Transient Ischemic Attack Patients with Fluctuations Are at Highest Risk for Early Stroke
Authors: Chatzikonstantinou Anastasios , Willmann Olaf , Jäger Theo , Szabo K. , Hennerici Michael G.
Published: April 2009

Background: The management and risk of early stroke are unclear in patients with fluctuating neurological symptoms. We aimed to evaluate the clinical course of these patients presenting within 24 h after onset of acute cerebral ischemia symptoms. Methods: All patients with transient ischemic signs/symptoms consecutively admitted to our Emergency Stroke Unit were recruited. Patients were neurologically examined and underwent prompt CCT plus MRI imaging for visualization of early signs of ischemia. Results: Among 122 patients, 84 (69%) had single symptoms, 33 (27%) showed rapidly relapsing and remitting symptoms – in 5 cases (4%) symptom duration could not reliably be assessed. 11/122 (9%) suffered a stroke during hospitalization. ABCD2 scores did not predict early strokes: 2/11 (18.2%) were in the ‘lower risk’, 7/11 (63.6%) in the ‘moderate risk’ and only 2/11 (18.2%) in the ‘high risk’ group (p = 0.103). 3/11 patients (27.3%) revealed lesions in neuroimaging, but surprisingly 8/11 (72.7%, p = 0.132) did not. However, patients with fluctuations in neurological status were significantly more likely to suffer a stroke: 9/122 versus 2/122 with stable symptoms (p < 0.05). Patients with small vessel disease were common in all (53/ 122; 43.4%) and within those who suffered an early stroke (6/11; 54.5%). Conclusions: Patients with unstable transient ischemic attacks immediately after onset of clinical symptoms are at high risk for subsequent stroke – they may benefit from Stroke Unit management and potential early thrombolysis once they develop strokes.
Oral Treatment of Hemophilia A Using Traditional Kanpo Medicine, Huang-lien-chieh-tu-tang (Plant Extract)
Authors: Adachihara Akiko
Published: April 2009

Huang-lien-chieh-tu-tang (HLCT) extract was given orally to a patient with severe hemophilia A. The plasma concentration of factor VIII rose from less than 1 to 41 % 1 h after oral administration of HLCT extract. APTT also decreased from 102.0 to 70.9 s. In vitro experiments, HLCT showed factor VIII, IX and X biological activity at concentrations around 0.08%. There was no factor-VIII-antigen-related activity in HLCT.
Regulation of the Initiation of Coagulation by Factor VII
Authors: Nemerson Yale
Published: April 2009

Factor VII, a single-chain zymogen, has sufficient proteolytic activity to initiate blood coagulation. The reason that coagulation does not occur continuously is that the zymogen like its 2-chain derivative enzyme, factor VIIa, absolutely requires tissue factor. The latter, a lipid-dependent glycoprotein, is not normally present in the blood. Upon tissue injury, however, coagulation is initiated by the activation of factors IX and X. The relationship of these events to the possibility that hemophilia A and B are tissue factor-dependent diseases is discussed.
Factor VII Congenital Deficiency
Authors: Mariani G. , Mazzucconi M.G.
Published: April 2009

In congenital factor VII deficiency the clinical picture is related to the levels of factor VII coagulant activity; when factor VΠ:C levels are very low the bleeding episodes can occur frequently. The most frequent bleedings are menorrhagia and metrorrhagia in females and hemarthrosis in both sexes. There are 3 immunological variants of factor VII deficiency: VII-, VIIR and VII+. Conversely, the genetic variants are 2: one characterized by no discrepancy between VII:C and VII·Ag (found in the heterozygotes of VII- and VIIR variants) and the other, in which a discrepancy between VII:C and VIL·Ag is found (heterozygotes from VII+ kindreds). In factor VII deficiency, most commonly the human and ox tissue factors show the highest sensitivity to the coagulation defect, whereas the one extracted from rabbits is definitely less sensitive; the definition of functional variants is based upon a different reactivity to homologous and/or heterologous tissue thromboplastins. In no case was a PIVKA-VII-like protein found and none of the factor VII defective molecules reacted to the generation of important kallikrein activity.
Activation of Factor VII in Patients with Carcinoma of the Prostate
Authors: Deijk W.A. , van Dam-Mieras M.C.E. , Muller A.D.
Published: April 2009

A preliminary report suggests a correlation between metastatic prostate cancer and increased plasma factor Vila levels. Prostate cancer without metastases and prostate hypertrophy showed no clear pattern in factor VIla. Further investigations concerning the relation between metastatic cancer and clotting factors are in progress.
Half-Life Time and Control Frequency of Vitamin K-Dependent Coagulation Factors
Authors: van Dam-Mieras M.C.E. , Hemker H.C.
Published: April 2009

A short review about the place of coagulation factor VII in the initial phase of blood coagulation is given. A theoretical model describing the relationship between the half-life times of vitamin K-dependent coagulation factors and the control frequency of oral anticoagulation therapy is presented. The constraints that control frequency imposes on the type of determination to be carried out are discussed.
Metabolic Aspects and Viability of Heparin/CPDA-1-Stored Red Cell Concentrate as a By-Product of a High-Yield Factor VIII Production Method
Authors: de Jonge J. , Smit Sibinga C.T. , Das P.C.
Published: April 2009

As a by-product of a new high-yield method of production of freeze-dried factor VIII, red cell concentrate (RCC) containing a small amount of heparin besides CPDA-1 was studied. Compared to CPDA-1-stored RCC no difference was found in hematology parameters and 2,3-DPG levels during 28 days storage. Although still in the normal range for transfusion, ATP levels were significantly lower compared to CPDA-1-stored RCC after 30 days shelf life. A survival study with 51Cr-labelled red cells showed good recovery and normal red cell half-life. Rapid transfusion of heparin/CPDA-1 RCC in 6 volunteers did not have any effect on aPTT. Heparin could not be detected in posttransfusion plasma samples.
Protective Effect of Gabexate Mesilate against Experimental Disseminated Intravascular Coagulation in Rats
Authors: Yoshikawa Toshikazu , Furukawa Yasumasa , Murakami Masashi , Takemura Shuhei , Kondo Motoharu
Published: April 2009

Experimental disseminated intravascular coagulation (DIC) can be induced by 4 h sustained infusion of endotoxin at a dose of 100 mg/kg in rats. The experimental model of DIC in rats was used to study the preventive effect of gabexate mesilate (GM) against DIC. Before the infusion of endotoxin, 10-6, 10-3, 1, 10, 50 or 100 mg/kg of GM was injected intraperitoneally. The preventive effects against DIC were noted in all the parameters, such as fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count, and the number of renal glomeruli with fibrin thrombi, in rats treated with 1, 10 or 50 mg/kg of GM. From these results it was shown that GM inhibited the aggravation of endotoxin-induced experimental DIC in rats.
Fibrinogen ‘Haifa’ – A New Fibrinogen Variant
Authors: Brook J.G. , Tabori S. , Tatarsky I. , Hashmonai M. , Schramek A.
Published: April 2009

A 30-year-old female presenting with arterial occlusions of the lower limbs was discovered to have a markedly abnormal thrombin time and reptilase time. Further investigations revealed the presence of a qualitatively abnormal fibrinogen. Two other family members who were completely asymptomatic had similar defects. The abnormal fibrinogen has been characterized and found to be a new variant and as such designated fibrinogen ‘Haifa’.
Interaction of Subcomponent Clq and Collagen with Isolated Platelet Membranes in Platelet Aggregation
Authors: Csákó G. , Suba E.A. , Ohanian S.H.
Published: April 2009

Human platelet membranes were isolated by the glycerollysis technique. When tested by a turbidimetric method in the presence of fibrinogen and calcium ions, the membrane vesicles exhibited patterns of reactivity to collagen. As with human platelet-rich plasmas, the aggregating effects of collagen were inhibited by preincubating the membrane suspensions with hemolytically active human C1q. Upon addition to platelet-rich plasma, the isolated membranes reduced collagen-provoked platelet aggregation. This inhibitory effect was partially suspended by prior incubation of the membranes with native C1q. The results show that the receptors for collagen and C1q are preserved during the membrane isolation procedure and support the competitive nature of inhibition by C1q of collagen-induced platelet aggregation.
Optimal Efficiency of Human Platelet Shape Changes
Authors: Dubler Daniel , Deranleau David A. , Lüscher Ernst F.
Published: April 2009

The light scattering extinction coefficients and kinetic rate constant(s) for the disc to sphere and the sphere to (smaller) ‘spiny sphere’ shape changes induced in platelets by saturating amounts of ADP are compared at 31, 37 and 41 °C. Platelets exhibit optimum efficiency at 37 °C, as judged by not only the rates of the shape changes but also by alterations in the overall sizes and shapes of the three platelet forms. Unstimulated (discoid) platelets appear to be flatter at 37 °C, the disc to sphere reaction appears to be impaired at other than 37 °C, and the pseudopodia which characterize the final spiny sphere may be more prominent at 41 °C.
Human Antithrombin III Heterogeneity: A Study by Isoelectrofocusing and Crossed Immunoelectrofocusing
Authors: Leone G. , Valori V.M. , Cotumaccio R. , Massi G.
Published: April 2009

Isoelectrofocusing was carried out in the LKB Multiphor apparatus with pH 4–6.5 carrier ampholines using polyacrylamide gel slabs. Specimens of purified antithrombin III (AT-III), normal plasma and serum were isoelectrofocused. Microheterogeneity was shown by three preparations of purified AT; the protein was separated in at least six bands, three large bands were located in the pH range 4.9–5.2, one intermediate band at pH 4.85, other thinner bands were located in the pH range 4.55–4.80. The microheterogeneity of AT-III was confirmed in purified preparations as well as in plasma and in serum by crossed immunoelectrofocusing. The pattern of purified preparations, normal plasma and serum were very similar; only minor, quantitative differences were noticed. Plasma from a patient with congenital AT-III deficiency showed an abnormal pattern.
Effects of FUT-175, a New Synthetic Protease Inhibitor on Endotoxin-Induced Disseminated Intravascular Coagulation in Rats
Authors: Yoshikawa Toshikazu , Murakami Masashi , Furukawa Yasumasa , Kato Haruki , Takemura Shuhei , Kondo Motoharu
Published: April 2009

The effects of FUT-175 (6-amidino-2-naphthyl-4-guanidino benzoate-dimethanesulfonate), a new synthetic protease inhibitor, on endotoxin-induced experimental disseminated intravascular coagulation (DIC) were studied in rats. Experimental DIC was induced by a 4-hour sustained infusion of endotoxin at a dose of 100 mg/kg. The rats were infused continuously with FUT-175 at 0.001, 0.01, 0.1, 1.0 or 10.0 mg/kg into a femoral vein for 4 h. Simultaneously with the agent infusion, endotoxin (100 mg/kg/4 h) was administered into the contralateral femoral vein. A protective effect against DIC was noted in the rats treated with 0.01 or 0.1 mg/kg of FUT-175 in the following parameters: fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi. These results demonstrated that FUT-175 reduces the extent of changes of the coagulation parameters caused by DIC.
Diminished Osmotic and Chemically Induced Haemolysis of Human Erythrocytes following Exposure to Contrast Media Molecules
Authors: Paul J. , Freyria A.M. , Clendinnen G. , Amiel M. , Eloy R.
Published: April 2009

Radiocontrast molecules (RCM) used in coronaroangiography and/or urography diminished their osmotic fragility when they were incubated for 30 min with human erythrocytes. The shift of the osmotic fragility curve towards lower NaCl concentration is related to the hypertonicity of RCM, but in addition, at a given osmolality (100 ± 5 mosm/kg), RCM at the concentration of 4–10% v/v increase the resistance to osmotic lysis or even suppress it. Similar protection is observed towards erythrocyte lysis induced by a detergent (saponin), polyenic antibiotic (filipin) or non-polyenic cholesterol-specific agent (digitonin). The effect is (1) proportional to the amount of RCM present, (2) independent of hypertonicity of the molecule, and (3) related to the nature of acidic molecules. A weak insertion of RCM into the erythrocyte membrane is suggested since it was suppressed by a single washing of the cells.
Pulmonary Manifestations of Sjögren’s Syndrome
Authors: Shi Ju-Hong , Liu Hong-Rui , Xu Wen-Bing , Feng Rui-E. , Zhang Zhu-Hua , Tian Xin-Lun , Zhu Yuan-Jue
Published: April 2009

Background: Primary Sjögren’s syndrome (PSS) is associated with various histological patterns of interstitial lung disease. Although chest images and lung function studies showed that lung involvement predominantly occurs in small airways, pathological findings were not consistent with the results of high-resolution CT (HRCT) and lung function tests. Objectives: To investigate the pathological characteristics of PSS-associated interstitial lung disease (PSS-ILD) and their relationship with HRCT lung function tests. Methods: Fourteen patients diagnosed as PSS who underwent surgical lung biopsy in Peking Union Medical College Hospital from October 2000 to October 2006 were reviewed. Histopathologic findings, radiologic findings and lung function tests were analyzed. Results:The study included 13 women. The median age was 46 years. Most patients presented with dyspnea and cough. CT scans revealed bilateral ground-glass, consolidative, reticular and nodular opacities and cyst lesions. The histological patterns included nonspecific interstitial pneumonia (NSIP) cellular pattern associated with organizing pneumonia (OP), NSIP mixed pattern associated with OP, noncaseating granulomas, chronic bronchiolitis, follicular bronchiolitis, constrictive bronchiolitis, lymphocytic interstitial pneumonia associated with follicular bronchiolitis, NSIP mixed pattern associated with follicular bronchiolitis, NSIP mixed pattern coexisting with chronic bronchiolitis, OP associated with chronic bronchiolitis, and noncaseating granulomas coexisting with OP. Treatment included prednisone and cyclophosphamide. During the follow-up period (median 38 months), most patients improved or remained stable. The patient with constrictive bronchiolitis died from progression of primary disease. Conclusions: The histopathologic patterns of PSS-ILD included lung interstitial involvement and small airway involvement or both. Corticosteroid therapy combined with cyclophosphamide was administered with a favorable response in the majority of patients.
The Role of Plasma Fibronectin in Platelet Adhesion to Collagen
Authors: Balduini C.L. , Sinigaglia F. , Salvini P. , Balduini C.
Published: April 2009

Human washed platelets were eluted from columns of Sepharose 4B linked to different preparations of collagen in order to evaluate cell adhesion. Collagen preparations characterized by low and high affinity toward platelets were identified. In our experiments, fibronectin purified from human plasma modified platelet adhesiveness, though not dramatically. When washed platelets, resuspended in a buffer containing fibronectin, were filtered on a low-affinity collagen-Sepharose, a significant increase in their adhesion occurred. A similar modification could be observed when platelets were allowed to adhere to the same collagen-Sepharose preconditioned with fibronectin. The effect of fibronectin was otherwise negligible when the high-affinity collagen was used for the experiments.
Correlation between Changes Induced by Venous Occlusion on Factor VIII-von Willebrand Factor Components and Fibrinolytic Activity
Authors: Ponari O. , Pini M. , Poli T. , Potí R. , Dettori A.G.
Published: April 2009

The effects of standardized venous occlusion (VO) on factor VIII-von Willebrand factor (F VIII-VWF) components (F VIIL·C, F VIIIR:AG, F VIIIR:RCof) and on fibrinolytic activity were investigated in 45 healthy subjects, in 28 women on oral contraceptives, and in 78 patients with various chronic diseases (28 with peripheral arterial disease, 19 with liver cirrhosis, 13 with rheumatoid arthritis, and 18 with diabetes). All the three F VIII-VWF components showed highly significant increases, although not of the same magnitude, with consequent variations in the ratios between them. A significant activation of fibrinolysis was also demonstrated with both euglobulin lysis time (ELT) and diluted blood clot lysis time (DBCLT). A strong linear correlation between pre- and post-stasis values was recorded for all the F VIII-VWF components and for the two fibrinolysis tests. No significant relationship was, on the contrary, found between F VIII-VWF and fibrinolytic parameters.
Impairment of Primary Hemostasis and Platelet Function after Alcohol Ingestion in Man
Authors: Elmér O. , Göransson G. , Zoucas E.
Published: April 2009

The effect of alcohol ingestion on primary hemostasis was investigated in fasting healthy humans. Primary hemostasis was measured with the template bleeding time and platelet aggregation assayed with the turbidometric method. Blood was collected to study coagulation and fibrinolysis. 1 h after ingestion of 2 ml/kg body weight of 40% alcohol the plasma alcohol concentration was 19.3 ± 1.6 mmol/l. At this time there was a significant prolongation of the bleeding time accompanied by an impairment of platelet responsiveness to both collagen and ADP. A prolongation of the bleeding time and impairment of platelet function was also found 2 h after alcohol ingestion. Ingestion of this amount of alcohol did not affect parameters of coagulation or fibrinolysis. The data indicate that primary hemostasis is impaired in man after ingestion of moderate amounts of alcohol. This may explain the favorable effect of moderate alcohol consumption on ischemic heart disease but indicates an increased risk for patients with bleeding.
Micro-Activated Partial Thromboplastin Time in Diluted Capillary Blood
Authors: Zondag A.C.P. , van Zanen G.E.
Published: April 2009

A sensitive micromethod for estimating the activated partial thromboplastin time in diluted capillary blood with excellent reproducibility is presented, as are results of test conditions with regard to sampling, calcium concentration, osmolarity of the diluent and the influence of the packed cell volume.
Influence of Sex, Blood Group, Secretor Character, Smoking Habits, Acetylsalicylic Acid, Oral Contraceptives, Fasting and General Health State on Blood Coagulation Variables in Randomly Selected Young Adults
Authors: Wahlberg Thomas B. , Blombäck Margareta , Magnusson David
Published: April 2009

Blood samples were drawn from 129 randomly selected young adults. Intake of acetylsalicylic acid (ASA), contraceptive drugs, smoking habits and health state were registered. Males had significantly higher systolic blood pressure, shorter bleeding time and lower VIII:C. Smoking was only correlated to some variables assessed in the female group. Users of oral contraceptives smoked more, had a shorter bleeding time and higher fibrinogen levels. Factor VIIIR;Ag was elevated only in female smokers with blood group non-O. Non-secretors had shorter bleeding times and a tendency towards higher VIIIR:Ag.
The Inhibition of Platelet Prothrombinase Activity by Prostacyclin
Authors: Zwaal R.F.A. , Comfurius P. , Hemker H.C. , Bevers E.M.
Published: April 2009

Prostacyclin is able to inhibit the development of platelet prothrombinase activity. This inhibition, which also occurs with dibutyryl cAMP, is presumably due to the ability of prostacyclin to prevent the formation of a negatively charged phospholipid surface at the exterior half of the platelet membrane. Generation of this procoagulant surface, as induced by platelet activation with collagen plus thrombin, does not depend on thromboxane A2 formation.
Low Molecular Weight (LMW) Heparin Derivatives in Experimental Extra-Corporeal Circulation (ECC)
Authors: Aiach Marline , Dreyfus Gilles , Michaud Anne , Relland John , Murawski Monique , Leclerc Maurice , Carpentier Alain
Published: April 2009

Low molecular weight (LMW) heparin has been shown to prevent experimental venous thrombosis. In order to investigate its biological action and its potential use in open heart surgery, we have conducted an experimental study using extracorporeal circulation (ECC) in sheep as an experimental model. 18 sheep were randomly selected to receive either LMW heparin (2 mg/kg), high dose heparin (HD; 160 U/kg), or low dose heparin (LD; 60 U/kg). The HD heparin yielded the same circulating anti-activated factor X (anti-Xa) activities as the LMW heparin and the LD heparin yielded the same anti-thrombin activity. LMW heparin and HD heparin were both effective in preventing blood clotting in the ECC circuit, demonstrating the antithrombotic activity of the LMW heparin. Clotting in the circuit was observed following LD heparin administration showing that the efficacy of LMW heparin does not only rely upon its weak anti-activated partial thromboplastin time (APTT) and antithrombin activity. Fibrinogen, fibrinogen degradation products (FDP), factor V (F V), platelet count, antithrombin III (AT III), fast acting antiplasmin (AP) were evaluated during and after ECC. The defects in hemostasis were similar in the three groups. Conclusions were: (1) heparin chain depolymerization diminishes the anti-APTT activity without altering the antithrombotic property; (2) LMW heparin is an effective alternative to heparin in cardiac surgery; (3) the absence of postoperative circulating anti-APTT activity might be associated with a reduced incidence of hemorrhagic complication, but we were not able to demonstrate it.
A Simple Quantitative Estimate of the Function of Radiolabelled Platelets
Authors: Peters A.M. , Porta M. , Reavy H.J. , Cousins S. , Wardle J. , Lewis S.M.
Published: April 2009

The function ex vivo of autologous platelets, labelled with 111In, was evaluated at various times following injection by comparing the retention on foreign surfaces of radioactivity with the retention of total platelets (represented almost entirely by unlabelled and therefore unmanipulated platelets) after the application of fresh un-anticoagulated whole blood to (a) filter paper and (b) glass bead columns. Relative retentions were similar for the two materials, with labelled platelet retention being about 80% that of native platelet retention. Prior to injection, when labelled platelets were returned to an excess of freshly drawn whole blood, retention of radioactivity was greater than that of native platelets with a ratio significantly greater than that seen with labelled platelets tested ex vivo. Filter paper retention provides a simple technique which may be useful for the evaluation of labelled platelet function as a function of platelet age and also, with further standardisation, as an inexpensive rapid test of unlabelled platelet function.
The Effects of High Doses of Aspirin and Related Benzoic Acid Derivatives on Arterial Thrombosis in Male Rats
Authors: Killackey J.J.F. , Killackey B.A. , Philp R.B.
Published: April 2009

The antithrombotic effects of four compounds structurally related to aspirin (acetylsalicylic acid, ASA) were examined in a rat model of arterial thrombosis and compared to ASA. ASA had antithrombotic activity, but only at high doses (200 mg/kg), when carotid artery thrombosis was induced 15 min after intravenous drug administration. Lower doses were associated with augmented thrombus formation in some animals. 2-Propionyloxybenzoic acid, which has in vitro activities similar to ASA, caused similar in vivo effects, but was antithrombotic at 100 mg/kg. 3-Propionyloxybenzoic acid, which augments platelet function in vitro, and 3-methylphthalide, which inhibits biphasic adenosine diphosphate-induced platelet aggregation, had no statistically significant effects. 2-Acetoxybenzoic acid, which is a weak platelet aggregation and prostaglandin biosynthesis inhibitor, had antithrombotic activity at 100 and 200 mg/kg and was not associated with augmented thrombosis at lower doses as found with ASA. The pattern of antithrombotic activity of this series of compounds does not reflect in vitro effects on prostaglandin biosynthesis and indicates alternative mechanisms of antithrombotic activity.
Thromboplastin Synthesis in Endothelial Cells
Authors: Galdal Kjell Sverre
Published: April 2009

Endothelial cells (EC) in culture produce a procoagulant identified as thromboplastin when stimulated with 12–O-tetradecanoyl-phorbol-13-acetate, phytohemagglutinin, endotoxin, thrombin, histamine or epinephrine. Inducible thromboplastin generation most likely depends on de novo synthesis of RNA and the protein component of thromboplastin, apoprotein III. It is further probably regulated by intracellular mechanisms involving cAMP, transmethylation and calcium ions. The EC thromboplastin response is enhanced in lymphocyte-EC and platelet-EC cocultures and thromboplastin becomes partly available on the cell surface. Levels of procoagulant activity are reached which clearly may be of clinical importance if similar levels appear in vivo.
Intracellular Signal Mechanisms in Induction of Thromboplastin Synthesis
Authors: Lyberg T.
Published: April 2009

Thromboplastin production in human monocytes gains steadily increasing significance as a pathogenetic factor in relation to human disease. A vast variety of stimuli can cause the induction of thromboplastin synthesis in monocytes, apparently through plasma membrane perturbation. Some of the possible signal compounds conveying information from the membrane to the intracellular-responding apparatus have been studied. Available data allow the conclusion that changes in intracellular concentrations of Ca2+, cyclic nucleotides and arachidonic acid metabolites as well as transmethylation reactions are of importance and modulate the integrated response which leads to increased synthesis and insertion of apoprotein III (the protein component of thromboplastin) in the plasma membrane.
Regulation of Procoagulant Factors in Mononuclear Phagocytes
Authors: Dean Roger T. , Leoni Patricia , Rossi Bartira C.
Published: April 2009

Mononuclear phagocytes can be activated to develop enhanced expression of a wide range of macromolecules and mediators. Amongst these are several procoagulants, most notably thromboplastin. A variety of stimuli (particles, ligands for cell surface receptors, and some pharmacological agents) enhance procoagulant expression. We indicate that such enhancement may contribute to intra-and extravascular coagulation in several types of infections. We also point to the paucity of knowledge on the biosynthesis and intracellular transport of these procoagulants and speculate on the nature of the mechanisms involved.
Simple Screening Techniques for the Detection of Hypercoagulation
Authors: Zondag A.C.P. , Kolb A.M. , Muller A.D.
Published: April 2009

A number of new screening techniques to detect the tendency to hypercoagulability in children with familial hypercholesterolemia is presented. The use of Thrombokinetics (TKG®) and the introduction of a quotient as a new parameter are discussed. The new techniques are compared with the conventional methods. The link of an increased quotient with the activated stage of factor VII has been shown in a pilot study. For the definition of normal values there is a need of a normal pool which has been critically prepared.
Coagulation Proteins Showing Abnormal Electrophoretic Mobility in Commercial Concentrates of Factor VIII and Prothrombin Complex
Authors: Vicente V. , Alberca I. , Calles I. , Manso M. , Lopez Borrasca A.
Published: April 2009

Five commercial factor VIII (FVIII) concentrates and three prothrombin complex concentrates (PCC) were studied with reference to the qualitative evaluation of factors II, IX, fibronectin, α2-antiplasmin α2-AP), antithrombin III (AT-III) and subunits A and S of FXIII by crossed-immunoelectrophoresis (CIE) and von Willebrand factor antigen (vWF: Ag) by radio-CIE. This latter protein had a different pattern with the absence or a decrease of larger forms and the presence of a fast-moving precipitating peak, suggesting degradation of the vWF:Ag in FVIII concentrates. In contrast, the electrophoretic mobility of fibronectin, α2-AP and AT-III was normal. All PCC showed a more anodic mobility of factor IX. Α2-AP also exhibited a different electrophoretic pattern to that of normal plasma. Abnormality of AT-III was also found in heparin-binding studies. The techniques used in the purification procedures are probably the mechanism responsible for the partial denaturing of these proteins.
Ploidy Pattern of Megakaryocytes in Patients with Metastatic Tumors with and without Paraneoplastic Thrombosis and in Controls
Authors: Winkelmann M. , Stöckler J. , Grassmuck J. , Pfitzer P. , Schneider W.
Published: April 2009

In order to measure megakaryocyte DNA content in a greater number of well-defined patients, the use of bone marrow aspirates obtained postmortem is a basic requirement. We could show that the distinction between the ploidy classes in DNA histograms is possible until 18 h postmortem. Thus, bone marrow aspirates obtained up to 12 h after death can be expected to give reliable results. Megakaryocytes of the following patient groups were studied: 15 patients with metastatic tumors and paraneoplastic thrombosis, 15 patients with metastatic tumors without paraneoplastic thrombosis and 10 controls. An increased ploidization of the megakaryocytes was found in all 30 patients with metastatic tumors, independently of whether these patients suffer from thrombosis or not. Higher megakaryocyte ploidization, however, is correlated with a larger cytoplasmic mass of megakaryocytes, which leads to an increased platelet production. Besides an overcompensation for increased platelet consumption, a mitogenic or thrombopoietin-like factor produced by the tumor itself must be considered.
Platelet Responsiveness and Biosynthesis of Thromboxane and Prostacyclin in Response to in vitro Cocaine Treatment
Authors: Togna G. , Tempesta E. , Togna A.R. , Dolci N. , Cebo B. , Caprino L.
Published: April 2009

Preincubation of rabbit platelet-rich plasma with cocaine hydrochloride, at low and high concentrations, increased the platelet responsiveness to arachidonic acid, in terms of the aggregating response and the thromboxane production. The thromboxane levels released by collagen-stimulated platelets were increased after incubation with low concentrations of cocaine, while marked decreases were observed after incubation with high doses of cocaine. No effects on platelet aggregation induced by collagen and ADP were observed when low concentrations of cocaine were added; on the other hand, high doses of the anaesthetic were found to block the aggregating effects of these two agents. Specific studies showed cocaine to have an inhibitory activity on prostacyclin release when the aortic tissue was mechanically and thermically stimulated. By contrast, the prostacyclin synthesis by ‘exhausted’ aortic rings incubated with arachidonic acid appeared to be enhanced after addition of cocaine. These results lead us to believe that cocaine modifies both the Ca++ membrane binding and the extent of Ca++ influx, thereby increasing the permeability to arachidonic acid and altering the affinity of the membrane binding sites for the aggregating agents.
Treatment of Familial Antithrombin-III Deficiency with Danazol
Authors: Eyster Elaine , Parker Mark E.
Published: April 2009

3 individuals from 2 unrelated families with recurrent thromboses and quantitative deficiencies of antithrombin III (AT-III) were treated with danazol, 600 mg daily for 4 months. Significant increases of AT-III (p < 0.025) measured as heparin cofactor activity were noted in 1 female and 1 male patient. Failure to augment levels in the other male patient may have been due to poor absorption of the drug following small bowel resection for mesenteric infarction. Side effects of estrogen deficiency necessitated dosage reduction in the female patient. The 2 males experienced no adverse side effects except for prolongation of the prothrombin time in 1 who was receiving oral anticoagulants. We conclude that danazol causes a significant increase in some individuals with familial AT-III deficiency. Additional studies are necessary to determine whether this form of therapy may prove to be a suitable alternative to long-term anticoagulation and to assess the long-term clinical benefits in individuals with recurrent thrombosis.
Effect of Hypophysectomy on the Tissue and Blood Plasminogen Activator Activity in the Rat
Authors: Smokovitis A. , Hattey E. , Binder B.R.
Published: April 2009

The response of the fibrinolytic system to hypophysectomy in the rat was studied. 4 and 6 weeks after hypophysectomy the tissue plasminogen activator activity (PAA) was significantly increased in the intima of the aorta, slightly but significantly increased in the renal medulla, and significantly decreased in the vessels of the testis. No change in the PAA of the caudal vena cava, heart, lung and renal cortex was noted. Also, the tissue plasmin inhibition remained unchanged. No effect on the PAA in plasma euglobulin fractions was observed, whereas F VIII was slightly but not significantly decreased 6 weeks after hypophysectomy.
Investigations on the Effects of Heavy Water (D2O) on the Functional Activity of Human Platelets
Authors: Reuter Hans D. , Fischer Jürgen H. , Thiele Susanne
Published: April 2009

Heavy water (D2O) is able to activate or to inhibit biological systems and thus influences metabolism and functions of tissues and organs. On the basis of results obtained in preservation experiments performed on various organs, the effects of D2O on the functions of human platelets (retraction, spreading, aggregation induced by adrenaline, ADP and collagen) have been investigated. The effects of D2O, involving changes of membrane receptor conformation, binding strength of substances to their specific receptors, pH-values or enzyme activities, resulted in a significant decrease of ADP- and collagen-induced aggregation, while adrenaline-induced aggregation was significantly increased at the same D2O concentration. Retraction in the presence of D2O was significantly inhibited in a dose-related manner, while spreading was diminished, but not fully inhibited even by highest concentrations of D2O (95%).
On the Retraction of Collagen and Fibrin Induced by Normal, Defective and Modified Platelets
Authors: Jelenska M. , Kopeć M. , Breddin K.
Published: April 2009

Fibrin clot retraction (FCR) and collagen gel retraction (CGR) were studied in patients with inherited platelet defects, i.e. in Glanzmann’s thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly, giant platelet syndrome, as well as in patients with von Willebrand disease and factor XIII deficiency. FCR was abnormal only in thrombasthenia, while CGR was found to be reduced in 2 patients with Hermansky-Pudlak syndrome and in 4 out of 5 cases with von Willebrand disease. Both FCR and CGR were normal in May-Hegglin anomaly, giant platelet syndrome and severe factor XIII deficiency. In none of the examined bleeding disorders was a concomitant FCR and CGR reduction detected. Natural polyamines and anti-fibronectin antibodies did not affect platelet potency in FCR or CGR. Peroxidation of platelet membrane components by sodium periodate abolished the platelet-induced FCR and CGR. This effect was reversed by subsequent reduction by sodium borohydride.
Kinetics of Urokinase-Induced Thrombolysis in a Biphasic in vitro System
Authors: Iga Yoshiro , Stella Sylvia R. , Chandler Bleakley
Published: April 2009

The role and effect of added lys-plasminogen (lys-PLG) on urokinase-induced thrombolysis in an in vitro biphasic system were investigated. The kinetics of lysis of whole blood thrombi was followed in perfusion mediums of normal plasma, PLG-deficient plasma and normal saline using a high and a low concentration of urokinase (UK). The lysis of standard whole blood thrombi in whole blood perfusion mediums to which had been added UK alone or UK plus lys-PLG was compared to whole blood thrombi enriched with lys-PLG by incorporation during thrombus formation or by adsorption during perfusion. In addition, the kinetics of lysis of PLG-deficient fibrin thrombi perfused in PLG-deficient plasma or normal saline was studied when lys-PLG had been added to the thrombus, to the perfusion medium or to both thrombus and medium. In PLG-deficient plasma from which plasmin inhibitors had not been removed, thrombolysis was minimal even at a high concentration of UK. This effect could be neutralized, and to some extent, regulated, by lys-PLG enrichment of the medium. Both PLG-incorporated and PLG-adsorbed whole blood thrombi gave initial and sustained acceleration of UK-induced lysis in comparison with standard nontreated thrombi. It is concluded that in a blood-thrombus biphasic thrombolytic system induced by UK, there is interaction between the phases, and that PLG in both phases influences thrombolysis.
Hereditary Protein C Deficiency
Authors: Broekmans A.W.
Published: April 2009

Hereditary protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease. Heterozygotes are at risk for superficial thrombophlebitis, deep venous thrombosis and/or pulmonary embolism, which may occur without apparent cause at a young age. Other manifestations are cerebral venous thrombosis and mesenteric vein thrombosis. In severe, often homozygous, protein C deficiency, a purpura fulminans syndrome may occur shortly after birth, resulting in death due to extensive thrombosis, if it is not adequately treated. The thrombotic manifestations in heterzygotes are effectively prevented by coumarin therapy. However, in the initial phase of oral anticoagulant therapy, the patients have an increased risk for the development of coumarin-induced haemorrhagic skin necrosis. The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis.
Hereditary Protein S Deficiency
Authors: Bertina R.M.
Published: April 2009

Protein S is a vitamin K-dependent plasma protein that serves as a cofactor of activated protein C (APC) in its inhibitory action on activated factor V and factor VIII and in its stimulation of fibrinolytic activity. In plasma, part of the protein S is complexed with the C4b-binding protein. Only the free protein S has APC cofactor activity. In our laboratory, 30 patients from 8 nonrelated families were detected that fulfilled the criteria of an isolated protein S deficiency. All patients were heterozygotes for the defect that is inherited as an autosomal-dominant disorder. Patients with a protein S deficiency were found to be at risk for the development of venous thrombotic disease at a relatively young age.
Delayed Fibrinolysis: A Cause of Thrombosis?
Authors: Brommer E.J.P.
Published: April 2009

On a theoretical basis, delayed fibrinolysis has always been assumed to allow a harmless, or rather, useful clotting process to develop into manifest thrombosis. Since the early sixties, when most modern concepts on fibrinolysis were postulated, the evidence for a causal relationship between impaired fibrinolysis and venous thrombosis has not become much stronger. On the other hand, several observations indicate an association between impaired fibrinolysis and arterial thrombosis. Recent years have witnessed a flare-up of interest in fibrinolytic therapy, especially of acute coronary artery thrombosis, and thanks to the availability of human tissue-type plasminogen activator, expansion of its field of application is to be expected. However, with drugs for maintenance enhancement of fibrinolysis still being out of reach, we rely on the well-established oral anticoagulant regimen for the prophylaxis of thrombosis in patients with an obvious thrombotic disposition.
The Mechanism of Action of Oral Anticoagulants and Its Consequences for the Practice of Oral Anticoagulation
Authors: Hemker H.C. , Frank H.L.L.
Published: April 2009

A short review on the discovery of the relation between vitamin K and the synthesis of clotting factors and on the development of anticoagulant therapy is given. The pro-coagulant activity induced by vitamin K resides in the postribosomal modification of N-terminal glutamic acids in γ-COOH glutamic acids. The mode of action of oral anticoagulants is explained. The concentration-effect relations and the choice of an oral anticoagulant is discussed.
Optimal Therapeutic Anticoagulation
Authors: Loeliger E.A. , Broekmans A.W.
Published: April 2009

The relevant literature on the intensity of anticoagulation needed to prevent the development or growth of thrombi in patients at risk is reviewed. In case of elective surgery, prevention of venous thrombosis is easily attained with heparin or with coumarin alone, at levels of anticoagulation involving only a minor risk of bleeding complications. For posttraumatic prophylaxis, more intensive oral anticoagulation is required, similar to that for the management of active venous thrombosis, for which a combined heparin/coumarin regimen is proposed. A 90% reduction of the incidence of systemic emboli in patients with a high risk of developing intracardiac thrombosis requires high-intensity treatment with a target INR of 4. More intensive anticoagulation would be needed to obtain the same 90% protection in case of arterial (coronary) thrombosis. This is prohibited, however, by the rapidly increasing bleeding risk in cases with INR values > 5. With a target INR of 3.5 (sixty-Plus patients), the reinfarction rate will not be lowered by more than two thirds. Antiplatelet drugs given alone or in combination with anticoagulants have not been convincingly successful thus far in the prevention and treatment of thrombosis.
Lack of Exchange among Plasma Proteins in Narrow Spaces on Glass, Demonstrated with Metal Oxide Coatings
Authors: Vroman Leo , Adams Ann L. , Brakman Mirjam
Published: April 2009

Onto ‘activating’ surfaces, intact normal plasma deposits an overlapping sequence of proteins, each being desorbed by the next. Ultimately, high molecular weight kininogen (HMK) is deposited unless contact was too short, or space between 2 surfaces too narrow. Thus, injected between a glass slide and a convex lens, intact plasma will leave a disk of HMK with a center of fibrinogen. We describe here how the exchange of proteins on the surface can be demonstrated by staining the adsorbate with a metal oxide suspension. Subsequent flooding of the preparation with more normal plasma causes lift-off of the oxide where underlying fibrinogen is being displaced by the HMK of the newly applied plasma. Kininogen-deficient plasma fails to remove any oxide, while normal plasma can remove nearly all of the oxide and adsorbate, left on glass by HMK-deficient plasma.
How Does the Pivka Inhibitor Interfere with the One-Stage Prothrombin Time?
Authors: Talstad Ingebrigt
Published: April 2009

Thromboplastins which were highly (Thrombotest®) and slightly (Normotest®) sensitive to the Pivka (protein induced by vitamin K absence) inhibitor were selected in this study. The influence of the Pivka inhibitor increased with increasing sample size and decreasing packed cell volume; however, a satisfactory correction for the Pivka inhibitor was possible. The inhibitor explained the different coagulation activities in the various assays and also interfered with the ratio method of standardization.
Normal Values of Coagulation in Canine Blood
Authors: Zondag A.C.P. , Kolb A.M. , Bax N.M.A.
Published: April 2009

Differences in the coagulation patterns between humans and dogs and the lack of reagents in the veterinary field to control haemostasis require a modification of existing screening techniques. The adaptations which were applied and which are described in this paper consist of greater dilutions of the samples. Two modified screening techniques in blood and plasma are described. The normal values of the different clotting factors and thrombokinetics, (thrombokinetogram, T.K.G.®), using a normal beagle pool as a reference, are presented.
Comparison of the Antithrombotic and Haemorrhagic Effects of Heparin and a New Low Molecular Weight Heparin in Rats
Authors: Andriuoli G. , Mastacchi R. , Barbanti M. , Sarret M.
Published: April 2009

A new low molecular weight heparin (LMWH) and a conventional unfraction-ated heparin (H) were tested in rats for venous antithrombotic activity and bleeding tendency after intravenous administration. Both drugs showed antithrombotic activity, but LMWH at the low dosages tested (0.1 and 0.25 mg/kg) demonstrated significantly higher activity than H. In a rat bleeding time test (transection model) both heparins produced a prolonged bleeding time, but LMWH possessed significantly less potency than H at all the dosages tested. Ex vivo coagulation parameters (activated partial thromboplastin time and antiXa activity) were also evaluated: LMWH presented very low activity on the APTT test and a sustained antiXa activity, comparable to that of H.