bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of Retinal Neovascularization by Small-Interference RNA Targeting Erythropoietin
Authors: Xiong Si-Qi , Xia Xiao-Bo , Xu Hui-Zhuo , Jiang Jian
Published: April 2009

Objective: To observe the effect of inhibition of retinal neovascularization by small-interference RNA (siRNA) targeting erythropoietin (EPO). Method: Three siRNAs against EPO were designed and synthesized. Then they were transfected to NIH/3T3 cells by liposomes. RT-PCR and Western blot were used to evaluate the efficacy of siRNA in attenuating EPO expression in NIH/3T3 cells. One-week-old C57BL/6J mice were exposed to 75 ± 2% oxygen for 5 days, then they were returned to room air to induce retinal neovascularization. The siRNA type shown as most powerful in reducing EPO expression in vitro was intravitreally injected in the treatment group. Retinal neovascularization was evaluated by angiography with injection of fluorescein-dextran and quantification of neovascular proliferative retinopathy after 5 days in room air. Moreover, RT-PCR and immunoblot analysis were used to determine whether local administration of siRNA could affect the expression of EPO in murine retinas. Results: Among the 3 designed siRNAs (named siEPO1–3), siEPO2 is the most efficient in inhibiting EPO expression. In this murine model of oxygen-induced retinopathy, retinal neovascularization in the eyes with siEPO2 injection was significantly reduced compared with that of the contralateral control eyes. Similarly, histological analysis indicates that the number of neovascular nuclei protruding into the vitreous cavity was decreased compared to the control eyes. Furthermore, the expression of EPO in the retinas injected with siEPO2 was dramatically decreased. Conclusion: siRNA against EPO could inhibit experimental retinal neovascularization by reducing EPO expression in the retinas of mice. It may provide a powerful and novel therapeutic tool for ischemia-induced retinal diseases.
Using Telephone and Informant Assessments to Estimate Missing Modified Mini-Mental State Exam Scores and Rates of Cognitive Decline
Authors: Arnold Alice M. , Newman Anne B. , Dermond Norma , Haan Mary , Fitzpatrick Annette
Published: April 2009

Aim: To estimate an equivalent to the Modified Mini-Mental State Exam (3MSE), and to compare changes in the 3MSE with and without the estimated scores. Methods: Comparability study on a subset of 405 participants, aged ≥70 years, from the Cardiovascular Health Study (CHS), a longitudinal study in 4 United States communities. The 3MSE, the Telephone Interview for Cognitive Status (TICS) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were administered within 30 days of one another. Regression models were developed to predict the 3MSE score from the TICS and/or IQCODE, and the predicted values were used to estimate missing 3MSE scores in longitudinal follow-up of 4,274 CHS participants. Results: The TICS explained 67% of the variability in 3MSE scores, with a correlation of 0.82 between predicted and observed scores. The IQCODE alone was not a good estimate of 3MSE score, but improved the model fit when added to the TICS model. Using estimated 3MSE scores classified more participants with low cognition, and rates of decline were greater than when only the observed 3MSE scores were considered. Conclusions: 3MSE scores can be reliably estimated from the TICS, with or without the IQCODE. Incorporating these estimates captured more cognitive decline in older adults.
Clinical, Biochemical and Neuroimaging Parameters after Thrombolytic Therapy Predict Long-Term Stroke Outcome
Authors: Brouns Raf , Sheorajpanday Rishi , Kunnen Jan , De Surgeloose Didier , De Deyn Peter Paul
Published: April 2009

Introduction: We investigated the predictive value of standard neurological evaluation, a commercially available biomarker assay and neuroimaging in the subacute phase for outcome after thrombolytic therapy in ischemic stroke. Methods: Thirty-four consecutive ischemic stroke patients were evaluated by means of the NIH Stroke Scale (NIHSS72), the Triage® Stroke Panel (MMX72) and standardized infarct volumetry at 72 h after treatment with intravenous recombinant tissue plasminogen activator or intra-arterial urokinase. Outcome was assessed by the modified Rankin Scale (mRS) at 3 months after the stroke. Results: NIHSS72, MMX72 and infarct volume correlated significantly with the mRS score at month 3 and emerged as independent outcome predictors from logistic regression analysis. NIHSS72 is the best predictor for outcome, but its accuracy increases by 9 and 6% when combined with MMX72 and infarct volumetry, respectively. The combined use of NIHSS72 and MMX72 allows long-term outcome prediction with 97% accuracy, which is not further improved by infarct volumetry. Conclusions: Routine clinical evaluation, bedside testing of biochemical markers by the Triage Stroke Panel and infarct volumetry on neuroimaging at 72 h after thrombolytic therapy are predictors for long-term outcome of ischemic stroke patients. Clinical assessment is the most reliable parameter for outcome prediction, but its predictive value is substantially improved when combined with the biomarker panel.
Sleep and Vigilance Disorders in Pregnancy
Authors: Neau Jean-Philippe , Texier Bénédicte , Ingrand Pierre
Published: April 2009

Objectives: To describe different sleep disorders and daytime sleepiness in a French population of randomly selected young women during pregnancy and to evaluate the frequency of these sleep disorders according to the three trimesters of pregnancy. Methods: Cross-sectional design with retrospective survey of pre-pregnancy, symptoms and prospective survey of current symptoms. Mothers were interviewed during pregnancy with a questionnaire to evaluate their sleep before pregnancy and to assess alterations in their sleep according to the trimester. Results: 871 pregnant women completed the questionnaire. The rate of pregnant women with insomnia with non-refreshing sleep and frequent awakenings increases during the second and the third trimester reaching more than 75% of the women, essentially due to an urge to urinate, movements of the fetus, backache and restless legs syndrome. Snoring also increases throughout the pregnancy with more than 18% of them snoring every night. Conversely, more than 75% of the women complained of a decrease in their vigilance and a need to nap inreased during the pregnancy. Conclusions: The subjective quality of sleep is disturbed as early as the first trimester of pregnancy and increases throughout the pregnancy, except for excessive daytime sleepiness which was more frequent during the first trimester.
Increased Expression of Cell–Cell Signaling Genes by Stimulated Mononuclear Leukocytes in Patients with Previous Atherothrombotic Stroke
Authors: Grond-Ginsbach Caspar , Horstmann Solveig , Hummel Manuela , Wiest Tina , Honold Cornelius , Pfleger Karin , Hergenhahn Manfred , Hollstein Monika , Weninger Annette , Knyazev Yuri , Mansmann Ulrich , Wagner Simone , Grau Armin J.
Published: April 2009

Background/Aims: Inflammation plays an important role in atherosclerosis and stroke. Acute infections are recognized as trigger factors for ischemic stroke. Methods: In this whole genome expression profile study of 15 patients and 15 control subjects, we tested the hypothesis that patients with a history of atherothrombotic stroke show enhanced transcription of inflammatory genes in circulating leukocytes. RNA from unstimulated or lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed with Affymetrix U133A GeneChips using a pooling design. Expression of single genes and functional groups of genes was analyzed by global statistical tests. Results: A total of 10,197 probe sets showed positive calls. After correction for multiple testing no single probe set revealed significant differences either without or with LPS stimulation. However, significant global expression differences were found upon LPS stimulation for the group of genes that are involved in cell–cell signaling. Conclusion: LPS stimulation of PBMCs, a condition mimicking bacterial infection, induces differential expression of a group of cell–cell signaling genes in patients with previous atherothrombotic stroke. This finding can be caused by genetic differences between both groups, but acquired risk factors, medication and technical factors may also have contributed to the result.
Cognitive Dysfunction in Systemic Lupus Erythematosus: Prevalence and Correlates
Authors: Olazarán J. , López-Longo J. , Cruz I. , Bittini A. , Carreño L.
Published: April 2009

Little is known about the mechanisms and relevance of cognitive dysfunction in systemic lupus erythematosus (SLE) patients who never displayed major neuropsychiatric manifestations (nSLE). Thirty-one nSLE female patients and 31 cognitively healthy control women were recruited. Sociodemographic, clinical, neuropsychological and SLE-related markers were collected including cerebral perfusion by single-photon emission computed tomography. Prevalences of cognitive complaints were 22.6% in nSLE versus 6.5% in the control group (p = 0.147); respective prevalences of cognitive dysfunction were 32.3 versus 6.5% (p = 0.01). Within the nSLE group, all cognitive domains appeared similarly affected, and correlations were found between cognitive dysfunction and less skilled occupation (r = –0.41, p = 0.02) and between cognitive complaints and depressive symptoms (r = 0.35, p = 0.05). Cognitive dysfunction is rather frequent in nSLE and seems to negatively impinge on social functioning.
Thirty Neurological Eponyms Associated with the Nazi Era
Authors: Kondziella Daniel
Published: April 2009

In the 1920s, the neurosciences in Germany were world-class. Then came Hitler’s regime, and with it 2 distinct changes happened to the research milieus in Berlin and elsewhere. First, the persecution of Jews and others deprived Germany of many of its most outstanding scientists. Second, numerous German and Austrian physicians became active in National Socialist (NS)-euthanasia programs. In recent years, the medical community has become more aware of the ethical burden associated with eponyms derived from scientists of the Third Reich. Yet a list of these eponyms with emphasis on clinical neurology is still missing. This paper therefore reviews 30 neurological eponyms derived from 29 physicians who lived in the Nazi era. Among them are victims who were forced out of the country or murdered in concentration camps, protestors who risked their academic careers and often their lives, beneficiaries who published on brains from ‘euthanized’ children, and collaborators who were directly involved in the planning and execution of NS-euthanasia programs.
Subcutaneous Injection of Desmopressin (DDAVP): Evaluation of a New, More Concentrated Preparation
Authors: Köhler M. , Hellstern P. , Tarrach H. , Bambauer R. , Wenzel E. , Jutzler G.A.
Published: April 2009

A more concentrated desmopressin (DDAVP) preparation (40 µg/ml), which required small injection volumes (< 1 ml), was studied in a double-blind trial in 10 healthy volunteers, 12 patients with haemophilia A, and 8 patients with uraemic bleeding. DDAVP was administered by subcutaneous injection at a dose of 0.4 µg/kg body weight. In healthy subjects, peak levels of DDAVP ranging from 480 to 638 pg/ml were reached 1 h after the subcutaneous injection and DDAVP was eliminated with a mean half-life of 3.1 h. DDAVP produced a 2.5-fold (3.0-fold) increase of factor VIII·C (factor VIII·Ag) and a 1.9-fold (2.2-fold) increase of von Willebrand factor:Ag (ristocetin cofactor) over baseline levels. Additionally, a 2.1-fold increase of tissue-type plasminogen activator antigen was observed. Factor VIII and von Willebrand factor were rapidly eliminated with a half-life ranging from 1.3 to 5.7 h and from 1.1 to 11.4 h, respectively. In haemophilia A patients, DDAVP produced a 2.3-fold increase of factor VIII·C 1 h after the injection. DDAVP was given on 8 occasions for management of bleeding, and only in 1 patient did a wound haematoma (after herniotomia) occur. In 7 of the 8 patients with uraemia the bleeding time shortened, and in all patients an increase of platelet retention and a decrease of platelet count was observed (p < 0.05). No serious local or systemic untoward side effects were observed.
Low-Dose Danazol for Vascular Access and Dialyzer Thrombosis in Hemodialysis Patients
Authors: Al-Momen Abdul Kareem M. , Huraib Sameer O.
Published: April 2009

Four hemodialysis patients (1 male and 3 females, aged 29-40 years) with unusual recurrent vascular access or dialyzer thrombosis were studied to find out whether a hypercoagulable state exists. Measurements of euglobulin clot lysis time (ELT), fibrinogen, antithrombin III (AT III), protein C (PC), protein S (PS), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) were done. Results indicated that all patients had prolonged ELT, low tPA, elevated PAI, normal AT III, and PS. Three patients had elevated fibrinogen level and two had low PC. Danazol 200 mg orally once a day effectively prevented any further thrombosis. In 4 weeks’ time, all the abnormal coagulation studies normalized in addition to elevation of AT III, PC and PS. Only 1 female patient had a prolonged menstrual period, which was reversed by lowering the daily dose of danazol to 100 mg. No other side effects were encountered. These data indicate that hypofibrinolysis may play a major role in vascular access or dialyzer thrombosis and that low-dose danazol may provide an effective prophylaxis and treatment. Larger controlled studies are needed to confirm these findings.
Coagulopathy in Disseminated Intravascular Coagulation due to Abdominal Sepsis: Determination of Prothrombin Fragment 1+2 and Other Markers
Authors: Okamoto Kohji , Takaki Akira , Takeda Shigeaki , Katoh Hidenori , Ohsato Keiichi
Published: April 2009

To estimate the degree of coagulopathy in abdominal sepsis, we measured the plasma levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complex (TAT) and plasmin-Α2-plasmin inhibitor complex (PIC) by the enzyme-linked immunosorbent assay in 38 patients with disseminated intravascular coagulation (DIC). In 20 patients with DIC due to abdominal sepsis, plasma levels of F1+2, TAT and PIC were 2.6 nmol/l, 27.9 µg/l and 1.5 µg/ml, respectively, with a mean antithrombin III (AT III) activity of 41.7%. F1+2, TAT, PIC and AT III levels were 4.7 nmol/l, 75.8 µg/l, 8.8 µg/ml and 70.9% in 18 patients with DIC as the result of malignancy. Though AT III levels in DIC due to sepsis were lower than those in DIC due to malignancy, the levels of F1+2, TAT and PIC in the former were not significantly more increased than those in the latter. The plasma levels of F1+2 were positively correlated with TAT and PIC in DIC patients with malignancy; however, there was no correlation between F1+2 and TAT or PIC in DIC patients with sepsis. In addition, the levels of serum albumin in the two groups were similar. These results suggest that activation of coagulation and fibrinolytic systems may not be so prominent in cases of DIC due to abdominal sepsis, compared to related events in DIC due to malignancy. It is also suggested that the depletion of AT III in cases of sepsis is not only caused by a consumption related to intravascular coagulation or to an alternate distribution of protein. It may relate to nonspecific proteolytic degradation by granulocytic proteinases. F1+2 may be more suitable than TAT for the evaluation of the coagulopathy in DIC patients with sepsis.
Factor VIII Concentrates in HIV-1-Positive Hemophiliacs Is Pure Better?
Authors: Eichinger S. , Pabinger I. , Kyrle P.A. , Köller U. , Kier P. , Schneider B. , Lechner K.
Published: April 2009

39 human immunodeficiency-virus-1 (HIV-1 )-positive hemophiliacs who had been regularly treated with non-virus-inactivated intermediate-purity factor VIII concentrates were divided into two groups. Group A consisted of 21 patients with a CD4/CD8 cell ratio of less than 1.0 and group B of 18 patients with a CD4/CD8 cell ratio of greater than 1.0. All patients of group A were switched to a high-purity virus-inactivated factor VIII concentrate, whereas patients of group B continued to receive the intermediate-purity concentrate. There was no significant difference in the average decline of CD4 cells between the two groups during the observation period. 9 patients of group A and 4 patients of group B developed AIDS. 5 patients of group A but 11 patients of group B remained clinically asymptomatic. We conclude that the 15-fold increase in purity of the factor VIII concentrate had no apparent beneficial effect on the CD4 cell counts in this patient group.
Electrophoretic Studies on Molecular Defects of von Willebrand Factor and Platelet Glycoprotein llb-llla with Antibodies Produced in Egg Yolk from Laying Hens
Authors: Toti F. , Gachet C. , Ohlmann P. , Stierlé A. , Grunebaum L. , Wiesel M.-L. , Cazenave J.-P.
Published: April 2009

Immunoglobulins isolated from egg yolk (IgYs) are a convenient source of polyclonal antibodies. Their purification is simple and the yields important (50 mg immunoglobulins/egg). Nevertheless their biochemical characteristics are different from those of rabbit antibodies generally used for the study of molecular defects of plasmatic and platelet proteins. Provided standardization is achieved, IgYs can be used for immunoelectrophoresis, immunoprecipitation or immunoblotting assays. We describe here the electrophoretic and immunoblotting conditions employed to explore human plasmatic and platelet von Willebrand factor (vWF) and human platelet GP Ilb-IHa using IgYs. These two proteins are involved in primary hemostasis and their absence or abnormality is responsible for hereditary bleeding disorders. The methods were applied to the characterization of patients with vWF or GP Ilb-IIIa defects and compared to classical mammalian IgG immunoelectrophoretic techniques. Results were further confirmed by flow cytometric analysis.
Isolation of a Fibrinolytic Protease, M4, from Venom of Crotalus molossus molossus (Northern Blacktail Rattlesnake)
Authors: Rael Eppie D. , Martinez Marcos , Molina Oscar
Published: April 2009

M4, a fibrinolytic protease, was isolated from the venom of Crotalus molossus molossus. It has a pI of 9.6 and a molecular weight of 27,000. The protease hydrolyzes the AΑ and BΒ chains of fibrinogen, and the Α and Β chains of fibrin. This activity was inhibited by EDTA and restored by Ca2+ or Zn2+, but not Mg2+. The protease hydrolyzed hide powder azure and casein, but it had no effect on collagen, hyaluronic acid, complement or synthetic substrates for thrombin, plasmin or kallikrein. Subcutaneous injections into mice with doses as high as 100 µg did not cause hemorrhage. This protease may have therapeutic use as a thrombolytic agent.
Orgaran (Org 10172): Its Pharmacological Profile in Experimental Models
Authors: Meuleman D.G.
Published: April 2009

Orgaran is a mixture of glycosaminoglycans extracted from animal mucosa. It consists of heparan, dermatan and chondroitin sulfate; a small proportion of heparan sulfate (4%) has high affinity for antithrombin III (AT III). Orgaran is devoid of heparin or heparin fragments. Orgaran catalyses the inactivation of factor Xa and thrombin. Compared to heparin and most low-molecular-weight heparins, Orgaran has a much higher anti-Xa/anti-IIa ratio. The inactivation of factor Xa is mediated by AT III and that of thrombin by both AT III and heparin cofactor II. Compared to heparin, which is a strong inhibitor of thrombin generation, Orgaran has only moderate inhibitory effects on thrombin generation. Orgaran shows minimal or no effects on platelet function in vitro or in vivo. It inhibits the formation of various types of thrombi (clot-like and mixed thrombi) with approximately the same potency as heparin. Both the high- and low-affinity fraction for AT III contribute to the antithrombotic activity. In contrast to heparin, Orgaran does not inhibit platelet deposition in experimental mixed thrombi unless very high doses of the heparinoid are used. Orgaran is more efficacious than heparin in preventing the extension of established venous thrombosis. Orgaran promotes less bleeding-enhancing activity than heparin in various experimental models. In addition, compared to heparin, it has only minimal effects on platelet degranulation during hemostatic plug formation. In vivo studies in experimental animals have demonstrated that at equivalent anti-Xa doses, the effect of Orgaran on thrombosis inhibition lasts considerably longer than that of heparin; in contrast, the effect of Orgaran on bleeding is less marked and of much shorter duration than that seen with heparin. Based on these observations, Orgaran has a significantly better risk/benefit ratio than heparin.
Pharmacokinetic Considerations on Orgaran (Org 10172) Therapy
Authors: Danhof M. , de Boer A. , Magnani H.N. , Stiekema J.C.J.
Published: April 2009

Pharmacokinetic investigations on Orgaran (Org 10172) have been conducted by monitoring the following biological effects: plasma anti-Xa, anti-IIa and Ila-generation-inhibiting (IlaGI) activities. In addition, a limited number of studies were conducted on the basis of concentrations of the No-affinity glycosaminoglyc(uron)an (NoA-GAG) fraction as determined by a competitive binding assay. In humans, widely different pharmacokinetic profiles for various biological effects were observed, with relatively short elimination half-lives for the anti-IIa and IlaGI activites of 4.3 ± 3.5 and 6.7 ± 3.2 h, respectively, but a relatively long elimination half-life of anti-Xa activity of 24.5 ± 9.6 h. These differences in half-life mainly reflect differences in the rate of elimination of individual components of Orgaran. Rapid elimination of some of these components may explain why twice daily dosing is required for optimal thrombosis prophylaxis with Orgaran. In a comparative study in healthy male volunteers, the pharmacokinetics of the following low molecular weight heparin(oid)s were determined after intravenous administration: Orgaran (3,750 anti-Xa units), Fragmin (5,000 anti-Xa units), Fraxiparine (7,500 IC units) and Clexane (40 mg). Between these products, wide differences in pharmacokinetics were observed. Particularly, the half-lives of anti-Xa activity and IlaGI activity were much longer for Orgaran than for the other products. At the same time, a relatively low area under the curve of anti-IIa activity was observed. The absolute bioavailability of Orgaran following subcutaneous administration was determined on the basis of plasma anti-Xa and IlaGI activities and the NoA-GAG fraction concentrations. Absorption from subcutaneous tissues was found to be close to 100 %, which is significantly higher than of heparin; a finding which indicates that the subcutaneous route is reliable for the administration of Orgaran. The elimination of Orgaran components occurs by renal and possibly non-renal routes. With respect to anti-Xa activity, about 50% of the total clearance can be accounted for by urinary excretion. Therefore, in severe renal failure, a reduction of the maintenance dose of Orgaran would seem to be indicated. Studies on the influence of enzyme induction as a result of treatment with pentobarbital suggest that the pharmacokinetics of Lomoparan are relatively insensitive to changes in hepatic function. In a number of studies, the influence of conditions such as age, body weight and drug interactions were studied. Generally, only minor changes in the pharmacokinetic parameters of Orgaran were observed. It is concluded that the studies on the pharmacokinetics of Orgaran on the basis of its biological effects have been helpful in the development of guidleines for the optimal dosing in thrombosis prophylaxis.
Orgaran in Heparin-lnduced Thrombocytopenia
Authors: Chong B.H. , Magnani H.N.
Published: April 2009

Patients who develop heparin-induced thrombocytopenia (HIT) frequently need further anticoagulation to treat an ongoing thromboembolic problem or to prevent one. Orgaran (Org 10172), a low-molecular-weight (LMW) glycosaminoglycuronan, has shown a low frequency (10%) of cross-reactivity in vitro with sera containing the HIT antibody, in contrast to the much higher frequency of cross-reactivity (≈ 80%) shown by the LMW heparins. This paper summarises the results of intravenous or subcutaneous Orgaran treatment in 57 of 67 Australian patients, in whom the diagnosis of HIT was reasonably confirmed by exclusion of other causes of thrombocytopenia and by objective tests. The presenting indications for Orgaran were: continuous venovenous haemofiltration and haemodialysis (n = 21), thrombo-embolism treatment (n = 23), thrombo-embolism prophylaxis (n = 10), and anticoagulation for coronary artery by-pass graft (n = 4), peripheral by-pass graft surgery and plasmapheresis (n = 1 each). The results showed Orgaran to be a safe, well-tolerated, effective (successful treatment in over 90% of patients) anticoagulant in patients with a high thrombotic and/or bleeding risk even if critically ill and requiring haemofiltration. The complete results of the world-wide study in 161 patients confirmed not only these clinical findings in the subgroup of 57 Australian patients, but also the low cross-reactivity (12 %) of Orgaran with the HIT serum factor.
Orgaran in the Prevention of Deep Vein Thrombosis in Stroke Patients
Authors: Turpie A.G.G.
Published: April 2009

Venous thrombo-embolism is a common complication in patients with acute ischaemic stroke. Without prophylaxis, deep vein thrombosis occurs in 60-75% of patients with dense hemiplegia, usually in the paralyzed limb, and 1-2% suffer fatal pulmonary embolism. Orgaran (Org 10172, low-molecular-weight heparinoid) has been evaluated for the prevention of deep vein thrombosis in patients with acute ischaemic stroke in two studies. In a double-blind study, 75 patients were randomized to receive Orgaran (50 patients) in a loading dose of 1,000 anti-Xa units intravenously followed by 750 anti-Xa units subcutaneously 12-hourly or placebo (25 patients). Deep vein thrombosis occurred in 2 of 50 (4%) in the Orgaran group and 7 of 25 (28%) in the placebo group (p = 0.005). The corresponding rates for proximal deep vein thrombosis were 0 and 16 %, respectively (p = 0.01). There was one major haemorrhage in the treated group and one minor haemorrhage in the placebo group. In the second study, the safety and efficacy of Orgaran was compared with unfractionated heparin in the prevention of deep vein thrombosis in a double-blind randomized trial. Eighty-seven patients with marked lower limb paralysis secondary to stroke were randomized to receive Orgaran (45 patients) in a dose of 750 anti-factor Xa units subcutaneously 12-hourly or unfractionated heparin (42 patients) in a dose of 5,000 units subcutaneously 12-hourly. Venous thrombosis occurred in 4 of 45 (8.9%) of the Orgaran group and 13 of 42 (31 %) in the unfractionated heparin group (2p = 0.014). The corresponding rates for proximal vein thrombosis were 4.4 and 11.9%, respectively (2p = 0.255). There were no clinically significant haemorrhagic complications in either group. The frequency of haemorrhagic conversion of the infarct was 6.9% overall with no difference in the incidence between the two treatment groups (p& > 0.1). The results of these studies demonstrate that Orgaran is effective in deep vein thrombosis prophylaxis in patients with acute ischaemic stroke. Orgaran is more effective than standard low-dose heparin, and is recommended for the prevention of deep vein thrombosis in patients with acute ischamic stroke.
Studies of Org 10172 in Patients with Acute Ischemic Stroke
Authors: Adams, Jr. Harold P. , Woolson Robert F. , Biller José , Clarke William
Published: April 2009

This report presents data from pilot studies of Org 10172 in the management of patients with acute ischemic stroke. The studies have established a potentially optimal dosage and treatment regimen and have provided information for the development of a large randomized trial. The trial of Org 10172 in acute stroke treatment is now underway in the United States.
Orgaran in Hip Fracture Surgery
Authors: Bergqvist David
Published: April 2009

Two studies evaluating the effect of Orgaran prophylaxis on the incidence of postoperative thrombosis in hip fracture surgery are reported. In one Scandinavian study, dextran was used in the comparative group, and in the US study, warfarin was used. In both, Orgaran was significantly more effective in reducing the frequency of deep vein thrombosis without producing an increase in bleeding complications or other side effects.
Increase in the D-Dimer Levels during Treatment in Patients with Acute Myelogenous Leukemia
Authors: Velasco F. , Torres A. , Rojas R. , Alvarez M.A. , Gomez P. , Castillo D.
Published: April 2009

Plasma concentration of thrombin-antithrombin III complex (TAT), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), PAI-2, D-dimer complex and urokinase-plasminogen activator (u-PA) activity were studied in 30 patients with acute nonlymphoblastic leukemia (ANLL), before and during antileukemic therapy. Fifteen patients showed signs of disseminated intravascular coagulation (DIC), 10 of them classified as M3, 2 as M2 and 3 as M5 subtypes. The initial levels of TAT complex were elevated in all ANLL patients. This increase was more pronounced in patients with DIC (p < 0.05). TAT increased significantly during the treatment period in all cases. u-PA and PAI-1 levels were elevated but there were no statistically significant differences between patients with and without DIC. PAI-2 levels were below the limit of detection in controls and in patients. However, the initially elevated D-dimer complex levels were significantly higher in DIC cases (p < 0.01) and they increased during the treatment period. A significant and positive correlation between D-dimer and TAT complex values was found in DIC patients (r = 0.68, p < 0.001). The high TAT complex and D-dimer levels further increased during chemotherapy treatment strongly suggest a hypercoagulable state with secondary activation of fibrinolysis not severe enough to manifest itself as clinically evident DIC in the majority of cases.
Effect of Mental Stress on Platelet Function in Normal Subjects and in Patients with Coronary Artery Disease
Authors: Grignani Guido , Pacchiarini Lucia , Zucchella Marisa , Tacconi Fiorenzo , Canevari Attilia , Soffiantino Francesco , Tavazzi Luigi
Published: April 2009

We studied the effect of emotional stress (mental arithmetic for 10 min) in 10 postinfarction patients and in 10 age-matched apparently healthy subjects as controls. Blood samples for platelet function studies and for the determination of epinephrine levels in serum were taken in basal conditions, at the end of mental stress and after 30 min of recovery. Patients were studied twice, in washout of medications and after oral administration of dipyridamole, 200 mg twice a day for 6 consecutive days. Mental stress induced in patients significant increments in different hemodynamic parameters (heart rate, systolic blood pressure and diastolic blood pressure) and in serum epinephrine levels. Concomitantly, the test produced a significant increase in platelet aggregation (induced by 3 µM ADP or 1 µg/ml collagen), the formation of circulating platelet aggregates and an increase in plasma thromboxane B2 levels. Hemodynamic parameters and platelet function tests returned to baseline values after 30 min. Similar activation of hemodynamic parameters, similar increase in epinephrine levels and lower increase in platelet function by emotional stress were observed in control subjects. Treatment of patients with dipyridamole had no effect on stress-induced increase in hemodynamic parameters and epinephrine levels, but decreased stress-related platelet activation. These data can contribute to a better understanding of the complex relationships between psychosocial factors, the hemostatic system and vascular disease.
Antithrombotic Effect of Ticlopidine on He-Ne Laser-Induced Thrombus Formation in Rat Mesenteric Microvessels
Authors: Yamamoto J. , Ishii I. , Sasaki Y. , Nagamatsu Y. , Matsuda T. , Ando E.
Published: April 2009

The inhibitory effects of ticlopidine and acetylsalicylic acid (ASA) on thrombus formation in rat mesenteric microvessels were studied. The results were compared with the effect of the drugs on platelet aggregation in citrated whole blood. He-Ne laser-induced thrombus formation in arterioles and in venules was significantly inhibited by 100 mg/kg ticlopidine. In contrast, a higher dose of ASA (300 mg/kg) was needed to inhibit thrombus formation and the effects of ASA were observed only in arterioles and not in venules. In addition, although the inhibition by ASA in arterioles was not strong it followed a dose-dependent manner, suggesting that the differential effect of ASA on platelets and endothelium may not be evident in vivo. Ticlopidine and ASA strongly inhibited ADP-induced whole blood platelet aggregation, but not collagen- or thrombin-induced platelet aggregation.
Assessment of Whole-Blood Spontaneous Platelet Aggregation during Pregnancy Using an Impedance Particle Counter
Authors: van Hof A.C. , Ubachs J.M.H. , van Wersch J.W.J.
Published: April 2009

The slide test method of Velaskar and Chitre for determining platelet aggregation in whole blood after induction of aggregation was modified for spontaneous platelet aggregation and evaluated. The reproducibility was satisfactory (CV 1-3%). The results obtained with this method and the method of Velaskar were not significantly different. The Spearman rank correlation was 0.75 (p < 0.0001). We established reference values for the particle counter method and Velaskar’s method in pregnant and non-pregnant women; no significant change in spontaneous platelet aggregation was seen throughout pregnancy. In order to estimate the clinical value of the test in pregnancy, we followed up a number of pregnant patients with primary enhanced spontaneous whole-blood platelet aggregation before and after treatment with low-dose acetylsalicylic acid. The test was found to be suited for the detection of spontaneous whole-blood platelet aggregation and for the follow-up after treatment with acetylsalicylic acid. Further studies are necessary, however, to assess the predictive value of an aberrant test result during pregnancy.
Inactivation of Factor Va by Activated Protein C on Selected Human Tumor Cell Lines
Authors: Nakagaki Tomohiro , Sueyoshi Tatsuya , Kisiel Walter
Published: April 2009

Previous studies have demonstrated that platelets or aortic endothelial cells provide an appropriate surface that augments the proteolytic inactivation of factor Va by activated protein C (APC). We have examined the ability of three human tumor cell lines (HepG2, CAPAN-2 and J82) to support the inactivation of human factor Va by human APC in the presence and absence of human protein S. APC-mediated factor Va inactivation on these tumor cell lines was assessed by measuring the ability of residual cell-bound factor Va to augment the proteolytic activation of prothrombin by factor Xa. Each of the tumor cell lines studied supported factor Va inactivation by APC in the presence of calcium ions. HepG2 cell monolayers supported this reaction most effectively, with CAPAN-2 and J82 cell monolayers exhibiting moderate and weak effectiveness, respectively. Although not essential for this reaction, protein S moderately enhanced the rate of factor Va inactivation by APC on these tumor cell lines. In addition, pretreatment of each tumor cell line with rabbit antihuman protein S IgG had little, if any, effect on its ability to support factor Va inactivation by APC. Our data suggest that these, and perhaps other, tumor cells can provide an appropriate phospholipid surface for promoting factor Va binding and rapid inactivation by APC.
Interferon-Gamma-lnduced Expression of Tissue Factor Activity during Human Monocyte to Macrophage Maturation
Authors: Scheibenbogen Carmen , Moser Heinrich , Krause Stefan , Andreesen Reinhard
Published: April 2009

The expression of tissue factor (TF) during differentiation of human monocytes (MO) to macrophages (MAC) in vitro is investigated in this study. In MO, TF activity can be induced by the addition of lipopolysaccharides (LPS) as detected by Northern blot analysis and measured functionally as procoagulant activity (PCA), while IFNγ alone has only marginal stimulatory activity. During in vitro differentiation of MO into MAC, however, there is a steady increase in IFNγ-induced PCA with a maximum on day 7. While MO during the first 2 days in culture are more responsive to LPS, IFNγ becomes the prominent stimulus for mature MAC. The response to IFNγ is rapid with a peak within 6-8 h and a subsequent downregulation to baseline activity within 24 h. Our results demonstrate that IFNγ can effectively induce TF in human MAC and that its expression is developmentally regulated during MO to MAC maturation in vitro.
Imbalance between Thrombin and Plasmin Activity in Disseminated Intravascular Coagulation
Authors: Kario Kazuomi , Matsuo Takefumi , Kodama Kazuya , Matsuo Miyako , Yamamoto Katsuichirou , Kobayashi Hiroko
Published: April 2009

We investigated the imbalance between thrombin and plasmin activity in vivo with various grades of severity of disseminated intravascular coagulation (DIC) in relation to the underlying diseases. Plasma thrombin-antithrombin-III complex (TAT) and plasmin- Α2-antiplasmin complex (PAP) levels were measured in 133 blood samples obtained from patients with DIC. The TAT/PAP ratio was higher in patients with sepsis or solid cancer than in those with hematologic malignancies. In acute promyelocytic leukemia (APL), the TAT levels were the highest, but the PAP levels were even higher and the TAT/PAP ratio was the lowest. As for the severity of DIC, in mild DIC, both thrombin and plasmin activities were increased. In moderate DIC, the TAT/PAP ratio increased, and thrombin activity was much more predominant. However, in severe DIC, the ratio decreased, and plasmin activity became excessive. In 3 patients with acute myeloblastic leukemia, APL and pancreatic cancer, respectively, the PAP level remained high during heparin therapy although the TAT level was decreased. When tranexamic acid was given, the PAP level was selectively reduced, and the TAT/PAP ratio was markedly decreased along with clinical improvement. These results indicate that monitoring of the TAT/PAP ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulants and antifibrinolytic agents.
Increased Plasminogen Activator Inhibitor Activity in Survivors of Myocardial Infarction Is Associated with Metabolic Risk Factors of Atherosclerosis
Authors: Keber Irena , Keber Dušan
Published: April 2009

To assess the relationship between the fibrinolytic system and coronary risk factors, several fibrinolytic parameters were measured in 72 male survivors of myocardial infarction and in 53 age-matched healthy controls. The coronary patients had significantly higher plasminogen activator inhibitor (PAI) activity than the control subjects, while t-PA antigen did not differ between the groups. After stratifying the coronary patients in 14 diabetic and 58 nondiabetic patients, the elevated PAI activity remained limited to the diabetic group. PAI activity correlated significantly with systolic blood pressure, blood glucose, body mass index and LDL cholesterol. In multivariate regression analysis, significant associations persisted between PAI and diabetes, body mass index and LDL cholesterol. Coronary disease had no impact on the regression model. Our results suggest that the increased PAI-1 in selected groups of coronary patients is not a consequence of coronary disease itself, but is rather related to the metabolic risk factors of atherosclerosis, especially diabetes.
Magnetic Resonance Imaging of Retracted and Nonretracted Blood Clots during Fibrinolysis in vitro
Authors: Blinc A. , Keber D. , Lahajnar G. , Zupančič I. , Zorec-Karlovšek M. , Demsar F.
Published: April 2009

Magnetic resonance imaging (MRI) of retracted blood clots embedded in nonretracted clots was used to follow their lysis with urokinase in a plasma milieu in vitro. The two types of clots that were imaged in the same plane differed in signal intensity on T2-weighted spin echo MR images throughout the 20-hour observation period. It was thus possible to delineate the contours of both clot types and measure their relative sizes by digital image processing. Lysis of retracted clots proceeded significantly slower than lysis of nonretracted clots. Our in vitro results suggest that MRI might prove useful in detecting thrombus retraction in vivo and in predicting the outcome of thrombolytic therapy.
Interaction of Platelets with Subendothelium in Rats Treated with PCA-4230, a New Antithrombotic Agent
Authors: Gutiérrez Díaz J.A. , Tolón R.M. , Sunkel C. , Priego J.G. , Ortega M.P.
Published: April 2009

The effects of a new antithrombotic compound, PCA-4230, versus ticlopidine were investigated using an experimental thrombosis and vascular endothelial injury model in rats. Both PCA-4230 and ticlopidine protected rat arteries from the formation of prominent thrombi and most of microthrombi without modifying the formation of a first platelet monolayer. Neither coagulation parameters nor fibrinolysis were “modified by these antithrombotic drugs. Neither PCA-4230 nor ticlopidine affected thromboxane A? production in rats, whereas unlike PCA-4230, ticlopidine inhibited ex vivo fibrinogen binding to the fibrinogen receptor found on the platelet membrane. In conclusion, PCA-4230 and ticlopidine inhibited thrombus formation in vivo by a platelet-dependent mechanism which may be different for one or the other drug in spite of the fact that the protective effect measured in this thrombosis model is quite similar for either PCA-4230 or ticlopidine. The above-mentioned results clearly show that PCA-4230 is a new potent agent with both antivascular-damaging and antiplatelet activities, and devoid of effects on coagulation and fibrinolytic systems.
Potential Influence of Observer Variation in Thromboprophylactic Trials
Authors: Wille-Jørgensen Peer , Borris Lars C. , Lassen Michael Rud , Jørgensen Lars Nannestad , Hauch Ole , Nehen Anne Marie , Kjœr Lasse , Jensen René
Published: April 2009

In order to investigate the influence of the interpretation of a postoperative venography, used as the scientific tool in a thromboprophylactic trial, twelve different evaluations of the same venography have been compared. Two hundred and nineteen patients, undergoing total hip replacement, fulfilled a randomized trial evaluating two different prophylactic regimens. Bilateral venography was performed 7-11 days after surgery, and the result of venography was defined as with or without deep venous thrombosis (DVT), irrespective of the location of a thrombus. The venograms were evaluated five times by different interpreters, and the criteria for the presence of DVT were recorded whether or not thrombi in minor veins were present. The incidences of DVT in the two prophylactic groups varied from 2.7 to 20.3% and from 13.5 to 34.2%, respectively, according to the diagnostic criteria. However, the risk reduction between the two groups was almost constant, no matter which type of evaluation was applied (7.9-15.1 %), and was statistically significant at the 5 % level in all but 4 of the 12 evaluations. It is concluded that despite uniformity in patient selection, the incidence of DVT is not uniform, even though it is stated that venography is used as the end point. The obvious interobserver variation did not change the conclusion when two regimens are compared in a specific randomized study.
Elastase Activity in Leukemic Cells
Authors: Törnebohm Eva , Lockner Dieter , Paul Christer , Egberg Nils
Published: April 2009

Elastase, a proteolytic enzyme which digests different clotting factors, has previously been isolated from monocytes, macrophages and granulocytes. In the present work, we have isolated leukemic cells from 1 patient with acute lymphoblastic leukemia (ALL) and from 6 patients with acute nonlymphoblastic leukemia. Detectable elastase activity was found in the cells from all patients with acute nonlymphoblastic leukemia and ranged from 0.016 to 0.619 μkat/1/μg DNA. The highest elastase activity was found in 1 patient with promyelocytic leukemia (M3), and no activity was found in the cells from the patient with ALL. It is possible that elastase-mediated proteolysis of coagulation factors is the mechanism responsible for bleeding complications which are frequent in M3.
Hemostatic Effect of Platelet von Willebrand Factor
Authors: Castillo R. , Escolar G. , Monteagudo J. , Reverter J.C. , Ordinas A.
Published: April 2009

In type III von WiUebrand disease (vWD) patients, the bleeding time was only partially corrected or not modified after cryoprecipitate infusion, although the levels and the multimeric structure of plasma von WiUebrand factor (vWF) were normal. However, the adhesion of normal platelets on the vessel wall subendothelium in the presence of postinfusion patient plasma improved more significantly than the bleeding time. These results suggest a role of the vWF released from normal platelets which is absent in type III vWD platelets. In 5 patients transfusion of normal platelet concentrates performed 1 h after cryoprecipitate infusion without modification of the bleeding time &(> 30 min) normalized this parameter, and platelet adhesion to the subendothelium elicited a marked improvement. These last results confirm the suggestion that platelet vWF plays an important ‘in vivo’ role in the hemostatic process, particularly in patients suffering from severe vWD.
von Willebrand's Disease in Scandinavia and on Difficulties in Diagnosing von Willebrand's Disease Type I
Authors: Blombäck Margareta
Published: April 2009

The research on von Willebrand’s disease performed in Sweden and Finland since the late 1920s is reviewed. The difficulties in diagnosing mild von Willebrand’s disease, due to intra-individual variability, is discussed in relation to making correct pedigrees for genetic studies. As shown by some examples, new techniques for genetic studies will eliminate such difficulties and lead to better understanding of the pathogenesis.
Haemophilia Home Therapy
Authors: Jones Peter
Published: April 2009

Within the past 20 years, home therapy has become an accepted treatment for the majority of people with severe haemophilia in the developed world. The intravenous administration of blood products by suitably trained patients or their relatives has proved to be safe and effective. It allows for the early treatment of bleeding episodes before the appearance of physical signs. It results in reduced morbidity, especially in terms of reduction in long-term arthropathy, and in reduced socio-economic handicap. It is cost effective both in terms of savings in time previously lost from school or work and reduction of reliance on expensive hospital facilities. Home therapy forms a vital part of the overall comprehensive care of people with haemophilia and their families.
Long-Term Therapy and On-Demand Treatment of Children and Adolescents with Severe Haemophilia A: 12 Years of Experience
Authors: Brackmann H.-H. , Eickhoff H.J. , Oldenburg J. , Hammersterin U.
Published: April 2009

Between 1978 and 1989, a controlled study was performed on children and adolescents suffering from severe haemophilia A. Special attention was given to long-term therapy adjusted to the patients’ requirements. The clinical and the X-ray scores of the Orthopaedic Advisory Committee of the World Haemophilia Society were used to assess the orthopaedic findings. The present investigation is a 12-year follow-up study of 90 patients affected with severe forms of haemophilia A. All knee and ankle joints of the patients were evaluated. After 12 years, the clinical scores remained unchanged or had been improved (knees 94%, X-ray score 97, ankles 86, X-ray score 88).