bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Clinical Significance of Antiphospholipid Antibodies to Noncardiolipin Antigens in Systemic Lupus erythematosus
Authors: Toschi V. , Motta A. , Castelli C. , Gibelli S. , Cimminiello C. , Molaro G.L. , Gibelli A.
Published: April 2009

The specificity and immunoglobulin isotype distribution of antiphospholipid (aPL) antibodies have been evaluated in 68 patients with systemic lupus erythematosus (SLE) by ELISA which employed a panel of 7 different PL antigens. A total of 49 patients (72%) were positive for aPL antibodies of different isotypes and directed to one or more PL epitopes. Prevalence of IgG anticardiolipin (aCL, 37%) was similar to that of the other negatively charged PLs phosphatidylserine (PS, 35%), phosphatidylinositol (PI, 35%), phosphatidylglycerol (PG, 35%) and phosphatidic acid (PA, 40%); prevalence reduced to 9-12 % and 7-16 % respectively for IgM and IgA isotypes to the same antigens. aPL antibodies to the zwitterionic PLs phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were also observed, though their prevalence was lower than that demonstrated for negatively charged PLs. Of the 36 SLE patients who were aCL negative (53%), 17 (25% of all patients and 47% of aCL-negative patients) were positive for aPL antibodies of different isotypes to one or more non-CL epitopes. During a mean follow-up period of 30 months, 10 patients had deep vein thrombosis (DVT) with a total of 21 events. By χ2 test, a significant correlation was found between DVT and IgG aCL (p = 0.03) and between this event and the presence of lupus anticoagulant (LA) antibody (p = 0.04). However, stronger correlations were demonstrated between DVT and IgA aCL (p = 0.007), IgG anti-PS (p = 0.02), and IgA anti-PC, -PI and -PG (p = 0.02,0.003 and 0.02, respectively), whereas no correlation was found between thrombotic events and aPL antibodies with PE and PA specificities. In contrast, a significant correlation was demonstrated between aPL antibodies to the latter antigen and thrombocytopenia (p = 0.02). Moreover, a significant correlation was observed between the presence of LA and IgG and IgM aCL antibodies, IgG and IgM anti-PS, IgG anti-PI and IgG and IgA anti-PA, suggesting the possibility that LA activity could be mediated by different subsets of aPL antibodies heterogeneous for specificity and isotype. The complexity of our data indirectly explains some of the discrepancies often observed between solid-phase immunoassays and coagulation studies employed for aPL antibody detection and indicate the importance of aPL antibodies directed to non-CL epitopes as additional parameters to predict the occurrence of thrombotic events in SLE patients.
Effect of Recombinant Aprotinin on Platelet Activation in Patients Undergoing Open Heart Surgery
Authors: Matzdorff A.C. , Green D. , Cohen I. , Bauer K.D.
Published: April 2009

The hemostatic effect of recombinant (r)-aprotinin was studied in 41 patients undergoing cardiopulmonary bypass surgery. Flow cytometry was used to measure the expression of glycoprotein lb (GPlb) and α-granule membrane protein 140 (GMP-140) on platelets. Additional parameters studied were β-thromboglobulin (β-TG), fibrinogen, fibrinopeptide A, plas-minogen, platelet count, and the amount of postoperative chest tube drainage. Chest tube drainage was significantly less in the r-aprotinin-treated patients (p < 0.001). The percentage of platelets expressing GMP-140 increased to 9.7% in r-aprotinin patients and to 12.1 % in controls during the surgery. The difference between both groups was not significant. Both values returned to baseline the next day. GPlb expression decreased in both groups by 33-38% during the surgery and returned to baseline the next day. GPlb expression and the plasma concentrations of fibrinogen, fibrinopeptide A, β-TG, and plasminogen were not different in r-aprotinin and control patients. We conclude that r-aprotinin reduces blood loss during cardiopulmonary bypass surgery, but the primary mechanism is likely not through a protective effect on platelets.
Coagulation Study in Patients Who Had Undergone Surgery for Meningioma
Authors: Dragoni F. , Mazzucconi M.G. , Acqui M. , Ferrante L. , Rosa G. , Mastronardi L. , Chistolini A. , De Sanctis V. , Mandelli F.
Published: April 2009

Abnormal fibrinolysis and thrombotic complications have been often observed in patients who had undergone surgery for meningioma. Fourteen patients, affected by meningioma, were studied before surgery, during surgery and 24 h after surgery in order to evaluate the modifications of the fibrinolysis system and the coagulation physiological inhibitors. Before surgery, no patient showed hyperfibrinolysis and/or modifications of coagulation physiological inhibitors. During surgery, an activation of fibrinolysis with pathological levels of tissue plasminogen activator activity (x = 6.33 U/dl, SD = 7.9, p = 0.02) and increased levels of fibrin degradation products (x = 0.21, SD = 0.18, p = 0.002) was noted. Modifications of the fibrinolysis parameters occurred only in 9/14 patients (64%). These patients presented a more vascularized tumour, revealed before surgery by computerized tomography scan and cerebral arteriography and directly confirmed during the resection. Twenty-four hours after surgery no patient presented fibrinolysis activation. There was no evidence of disseminated intravascular coagulation in our patients. None of them presented pathological decrease of the physiological coagulation inhibitors or thrombotic complications. In conclusion, during surgery, fibrinolysis parameters show important modifications in patients with vascularized meningioma suggesting an ongoing tumour-host interaction. These variations must be taken in account, in order to plan timely a correct therapeutic approach.
Effect of Low-Dose Heparin Treatment on Fibrinolysis in Patients with Previous Myocardial Infarction
Authors: Prisco Domenico , Paniccia Rita , Gensini Gian Franco , Coppo Mirella , Colella Andrea , Filippini Monica , Brunelli Tamara , Abbate Rosanna , Neri Serneri Gian Gastone
Published: April 2009

The present study was designed to investigate whether medium-term, low-dose heparin treatment is able to affect the fibrinolytic system. In a randomized cross-over study 10 asymptomatic patients with previous (1-6 years) myocardial infarction underwent two sequential 15-day treatments, respectively, on heparin and on placebo (saline solution), preceded and separated by 10-day wash-out periods. Heparin (as calcium heparin, 12,500 IU in 0.5 ml) and saline (0.5 ml) were subcutaneously administered once a day at 8 a.m. Blood samples for fibrinolysis studies were withdrawn on the first and 15th day of each period immediately before and 4 h after heparin or saline administration before and after 10 min venous occlusion (VO) respectively. Four hours after the first heparin administration tissue plasminogen activator antigen (t-PA ag) levels significantly increased with respect to saline administration (p < 0.01 and p < 0.05, respectively). After 15-day heparin treatment a decrease in euglobulin lysis time (p < 0.05) and an increase in t-PA activity (act) (p < 0.05) and in t-PA ag (p < 0.01) in comparison with placebo were observed before VO. No statistically significant changes in plasminogen activator inhibitor-1 (PAI-1) levels were found. The variations of fibrinolytic system activity induced by heparin treatment were more marked when evaluated after VO. These results indicate that medium-term low-dose heparin treatment increases t-PA ag formation and/or release with consequent t-PA act increase.
Lack of Anti-Factor Xa Activity in Umbilical Cord Vein Samples after Subcutaneous Administration of Heparin or Low Molecular Mass Heparin in Pregnant Women
Authors: Harenberg J. , Schneider D. , Heilmann L. , Wolf H.
Published: April 2009

Prophylaxis of thromboembolism with low molecular mass (LMM) heparin may offer several advantages over conventional heparin during pregnancy. Heparin-related side effects as osteoporosis, local allergy, thrombocytopenia and increase in liver enzymes may occur less frequently with LMM heparin. However, LMM heparins of different origins have to be considered as individual pharmaceutical compounds. This is of special clinical importance regarding a possible placental passage. We performed a randomized controlled study comparing the anti-factor Xa activities in plasma samples of 60 pregnant women undergoing delivery at term and in the umbilical cord vein of the newborn after subcutaneous administration of 5,000 IU unfractionated (UF) heparin or 1,500 activated partial thromboplastin time units LMM heparin or placebo. Injections were performed about 2 h prior to the delivery. Maternal and fetal blood samples were taken at the same time to assay heparin activity by the heptest coagulation assay and the S2222 chromogenic substrate method. LMM heparin was detected in all maternal plasma samples whereas UF heparin was measurable only in about one third of them. UF heparin as well as LMM heparin were not detectable in samples taken from the umbilical cord vein. The data demonstrate that neither UF nor the LMM heparin used in this study cross the placenta in relevant inhibitory activity towards factor Xa. This finding is in accordance with the previous experiences regarding the safe administration of other LMM heparins for prophylaxis of thromboembolism during pregnancy.
Influence of Age, Sex and ABO Blood Group on Activated Partial Thromboplastin Time
Authors: Fourel V. , Gabastou J.M. , Desroys du Roure F. , Ehrhardt N. , Robert A.
Published: April 2009

To evaluate the influence of age, sex and ABO blood group on the activated partial thromboplastin time (APTT), we performed this test in 642 preoperative ambulant adult subjects. There was a significant negative correlation (R = 0.31, p < 0.001) between age and APTT. Sex and ABO blood group had a significant influence on APTT, with lower mean in females (30.9 s) and non-0 subjects (30.7 s) than in males (31.6 s) and·subjects (32.0 s) (p = 0.015 and < 0.001, respectively). The largest difference between the upper cut-off values of APTT determined in patient subgroups defined on age, sex and ABO blood group is observed for non-O females over 40 years (36.9 s) and·males under 40 years (41.1 s). These results emphasize the laboratory’s difficulties to define valid APTT normal range and thus to detect true mild coagulation disorders in preoperative asymptomatic patients.
Effect of Pre-lncubation at 37°C of Platelet Concentrates on the Post-Transfusion Platelet Adhesion Capacity to Collagen and Fibrinogen
Authors: Boomgaard M.N. , Stulp J.G. , de Korte D. , Pietersz R.N.I. , Reesink H.W. , Huijgens P.C. , Loos J.A.
Published: April 2009

The effect of warming (37 °C) of stored platelet concentrates (PC) on the post-transfusion platelet function as measured by the adhesion capacity in a rectangular perfusion system under flow conditions was analyzed in 22 patients undergoing transfusion for stable thrombocytopenia. Nine patients received a PC stored at 22 ° C and incubated at 37 ° C for 1 h before transfusion, 10 patients received a non-warmed PC, 3 patients received both a pre-warmed and a non-warmed PC. In the PC the platelet adhesion capacity to collagen was higher in the pre-warmed PC than in the non-warmed PC (33 ± 5.9% coverage vs. 22 ± 4.7% coverage, respectively, in a selected group with the same platelet concentration). The adhesion capacity to collagen of the platelets in the patient’s blood, measured 10 min after transfusion, had increased considerably in both patient groups and 4 h later the adhesion capacity in both patient groups was similar to that of the pre-warmed PC before transfusion. We conclude that though pre-warming of stored PC had a beneficial effect on the adhesion capacity to collagen of the platelets in the PC, the clinical significance is questionable because already 10 min after transfusion the adhesion capacity to collagen of stored non-warmed platelets had improved to the level of the pre-warmed platelets and 4 h after transfusion this improvement was still present.
Therapeutic Use of Low-Molecular-Weight Heparins
Authors: Hull Russell D. , Pineo Graham F.
Published: April 2009

Accumulating evidence indicates that certain low-molecular-weight (LMW) heparins administered subcutaneously may replace classic intravenous heparin therapy. LMW heparins do not require monitoring and may be safer and more effective than unfractionated heparin. The decreased mortality rate, evident in two randomized trials, which was particularly striking in patients with metastatic carcinoma, requires confirmation. The simplified care offered by LMW heparin therapy raises the possibility of transferring care from in-hospital to out of hospital in uncomplicated patients with deep-vein thrombosis [Salzman EW: Low-molecular weight heparin and other new antithrombotic drugs. N Engl J Med 1992;326: 1017-1019]. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient LMW heparin therapy will likely prove to be highly cost-effective. It is uncertain at present whether the findings associated with an individual LMW heparin preparation can be extrapolated to a different LMW heparin. For this reason the findings of clinical trials apply only to the particular LMW heparin evaluated and cannot be generalized to the LMW heparins at large.
Is There a Need for Long-Term Thromboprophylaxis following General Surgery?
Authors: Wille-Jørgensen Peer , Lausen Iver , Nannestad Jørgensen Lars
Published: April 2009

Thromboprophylaxis to surgical patients is generally accepted, and used in the perioperative period by many surgeons as effective means of reducing postoperative thromboembolic complications. Often the prophylaxis is stopped at the time of mobilization or discharge of the patient, although late thromboembolic complications after cessation of the postoperative prophylaxis are known to occur up to 7 weeks after surgery. By scrutinizing thromboprophylactic studies performed in general surgery during the last 20 years, we found the incidence of late thromboembolic complications reported to be about 1 % when clinical diagnostics was applied. In studies where the patients were screened for late thromboembolic complications using paraclinical diagnostic methods the incidence is 10 times higher. The clinical relevance of these late postoperative thromboembolic complications is still uncertain, as is the value of long-term prophylaxis.
Incidence and Prophylaxis of Deep Venous Thrombosis in Outpatients with Injury of the Lower Limb
Authors: Kujath P. , Spannagel U. , Habscheid W.
Published: April 2009

253 outpatients were included in a prospective randomized study. All patients had incidences of injuries of the lower limb immobilized by a plaster cast. 126 patients (group I) received a subcutaneous injection of Fraxiparin daily, and 127 patients (group II) received no thromboprophylaxis. Without prophylaxis 21 (16.5%) cases developed a thrombosis, and with prophylaxis a thrombosis could be proven in 6 (4.8%) patients only (p < 0.01). Thus, for all patients with an injury of the lower limb being immobilized by a plaster cast, a thromboprophylaxis with a low-molecular-weight heparin is recommended.
Long-Term Prophylaxis following Orthopedic Surgery
Authors: Bergqvist David
Published: April 2009

Recently there has been an increasing interest in long-term prophylaxis as it has become known that thromboembolic events may occur fairly late in the postoperative course. However, the scientific knowledge on long-term prophylaxis is small and adequately performed studies must be done before general recommendations are made.
Long-Term Oral Anticoagulant Therapy for Coronary Artery Disease
Authors: Raskob Gary E.
Published: April 2009

The findings of recent clinical trials have led to renewed interest in the role of oral anticoagulant therapy in patients with coronary artery disease. However, there are currently two major limitations to the routine use of oral anticoagulant therapy. The first is the need for laboratory monitoring and dose adjustment. This limitation may be overcome if fixed low doses of warfarin (e.g. 1 mg/day), which have antithrombotic effects, are shown by clinical trials to be effective and safe. A second limitation to oral anticoagulant therapy is uncertainty about its effectiveness and safety compared to aspirin, or in combination with aspirin. The current pathophysiologic knowledge and recent clinical trial data provide support for further clinical trials evaluating combined warfarin and aspirin treatment in the long-term care of patients with coronary artery disease, and in the primary prevention of myocardial infarction.
Thromboprophylaxis in Emergency Surgery
Authors: Bergqvist David , Flordal Per Anders , Friberg Bertil , Frisell Jan , Hedberg Mats , Ljungström Karl-Gösta , Mätzsch Thomas , Törngren Staffan
Published: April 2009

Except for hip fracture surgery, emergency surgery has been only exceptionally studied concerning thromboprophylaxis. There are, however, several reasons to believe the frequency to be fairly high and that the patient group would be in need of prophylaxis. This paper discusses various emergency situations and also gives the design for an ongoing controlled study on the effect of postoperative start of thromboprophylaxis with low molecular weight heparin in emergency abdominal surgery.
Screening and Diagnosis of Deep Vein Thrombosis and Pulmonary Embolism
Authors: Bergqvist David
Published: April 2009

Clinical diagnosis of deep vein thrombosis and pulmonary embolism is difficult. Therefore objective tests are necessary. This paper discusses the principal viewpoints on which criteria can be used for various tests and how new methods should be evaluated.
Duplex Scanning in Post-Operative Surgical Patients
Authors: Nicolaides Andrew , Kalodiki Evi
Published: April 2009

The technique of duplex scanning for the diagnosis of deep venous thrombosis (DVT) has been developed in 3 stages. Initially B-mode imaging with compression was used. Subsequently interrogation of the venous lumen using the Doppler facility was introduced and finally the latter became simple and efficient with the introduction of colour flow imaging. Sensitivities and specificities in excess of 90% have been produced for thrombosis proximal to the calf by all methods in symptomatic patients. Colour flow imaging has given the best results for calf DVT in symptomatic patients with 86% sensitivity and 91% specificity. Before the introduction of colour flow imaging the accuracy for the detection of old thrombi in asymptomatic patients was poor. With the introduction of colour, sensitivities and specificities in excess of 90% have been obtained for proximal DVT; for calf DVT, sensitivity of 79% and specificity of 97% have been reported by 2 studies. If further studies substantiate these recent results duplex scanning will become the non-invasive method to be used in screening asymptomatic patients.
Factor Xa Inhibition: Correlation between the Plasma Levels of Anti-Xa Activity and Occurrence of Thrombosis and Haemorrhage
Authors: Leizorovicz A. , Bara L. , Samama M.M. , Haugh M.C.
Published: April 2009

A multicentre, double-blind, randomised trial was conducted to compare the efficacy of a low-molecular-weight (LMW) heparin, Logiparin, with that of an unfractionated (UF) heparin in the prophylactic treatment of thrombosis in patients undergoing general surgery. A total of 1,290 patients were randomised to receive a single daily dose of Logiparin (2,500 IU: 431 patients; 3,500 IU: 430 patients) or UF heparin (2 × 5,000 IU: 429 patients). The incidence of the main end point, deep venous thrombosis, was found to be significantly different between the groups (p = 0.03), whereas the incidence of severe haemorrhage was not (p = 0.5). The plasma anti-Xa activity was found to be correlated with body weight, but correlated only very weakly with antithrombotic activity (p = 0.045) after adjustment in a stepwise multivariate analysis, and did not significantly correlate with the incidence of haemorrhage. Logiparin at 3,500 IU and UF heparin showed similar efficacy. Although a correlation between plasma anti-Xa activity and body weight was observed, there is not sufficient evidence to recommend the adjustment of the Logiparin dose on patient’s weight for prophylaxis in general surgery patients.
Antithrombotic Activity and Its Relationship to in vitro Anticoagulant Effects
Authors: Gray Elaine , Padilla Ana , Barrowcliffe Trevor W.
Published: April 2009

Antithrombotic activities of low molecular weight heparins (LMWHs) in a venous stasis thrombosis model, when compared to unfractionated heparin (UFH), correlated better with anti-IIa activities and inhibition of thrombin generation than with anti-Xa activities. The relative antithrombotic potencies of LMWHs were closer to inhibitory activity in thrombin generation with platelet-poor plasma than platelet-rich plasma. Comparing activities in intrinsic and extrinsic systems, higher concentrations of heparins were required in vitro to inhibit intrinsic thrombin generation than extrinsic thrombin production; however, higher doses were required to prevent in vivo thrombotic events initiated via the extrinsic pathway.
Heparin / Low Molecular Weight Heparin Tissue factor Pathway Inhibitor
Authors: Abildgaard Ulrich
Published: April 2009

Tissue factor pathway inhibitor (TFPI) is the factor Xa (FXa)-dependent coagulation inhibitor. TFPI is released to the blood after injection of heparin or low molecular weight heparin (LMWH). The post-heparin anticoagulant effect is caused by this release of TFPI. Free TFPI has higher affinity for heparin than TFPI which is associated with lipoproteins. Heparin increases the rate of inactivation of FXa and of tissue factor-F VIla by TFPI. Immunoblocking of TFPI reduces the anticoagulant effect of heparin in blood activated by tissue factor considerably. Both antithrombin and TFPI participate in the anticoagulant effect induced by heparinization of blood or plasma.
The Role of Oxygen Radicals in Human Disease, with Particular Reference to the Vascular System
Authors: Halliwell Barry
Published: April 2009

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other reactive oxygen species (ROS), such as hydrogen peroxide, are formed in vivo. Imbalance between production of ROS and anti-oxidant defence can result in oxidative stress, which may arise either from deficiencies of anti-oxidants (such as glutathione, ascorbate or α-tocopherol) and/or from increased formation of ROS. Oxidative stress can result in glutathione depletion, lipid peroxidation, membrane damage and DNA strand breaks as well as activation of proteases, nucleases and protein kinases. Some degree of oxidative stress occurs in most, if not all, human diseases, and the major question to be answered is whether it makes a significant contribution to the disease pathology. In the case of atherosclerosis, evidence from studies with the chain-breaking anti-oxidant probucol and from epidemiological work suggests that oxidative damage does indeed make an important contribution to plaque development.
Heparin and Angiogenesis: A Low-Molecular-Weight Fraction Inhibits and a High-Molecular-Weight Fraction Stimulates Angiogenesis Systemically
Authors: Norrby Klas
Published: April 2009

The systemic effect of 2.4-, 8-, 15- and 22-kDa heparin fractions on saline-mediated angiogenesis in rats was compared with the systemic effect of an unfractionated Na-standard heparin (UFH), which had a mean molecular weight of about 15 kDa. Using the mesenteric-window assay in adult rats, the relative vascularized area was quantified morphometrically. The angiogenic response was strictly related to the mean molecular weight of the saccharides (r = 0.97); the 2.4-kDa fraction suppressed angiogenesis by 46% (p ≤ 0.001), whereas the 22-kDa fraction stimulated angiogenesis by 123% (p ≤ 0.01), as compared with the UFH. The UFH, thus, contained chain-length-related fragments that induced systemic antiangiogenic and angiogenic activity.
New Aspects on Heparin and Lipoprotein Metabolism
Authors: Olivecrona Thomas , Bengtsson-Olivecrona Gunilla , Østergaard Per , Liu Guoqing , Chevreuil Olivier , Hultin Magnus
Published: April 2009

Lipoprotein lipase (LPL) and hepatic lipase (HL) are two enzymes which participate in metabolism of plasma lipoproteins. The enzymes are located at vascular surfaces and are released from their binding sites on injection of heparin. In this paper we give a short overview of the structure of the lipases and their role in lipoprotein metabolism. Earlier studies had shown that low molecular weight (LMW) heparin preparations result in lower LPL activities in blood than do corresponding amounts of conventional heparin. Studies with organ perfusion in rats show that the two types of heparin have similar ability to release the lipases from their binding sites in extrahepatic tissues, but that LMW heparin is less effective than conventional heparin in preventing rapid uptake and degradation of LPL by the liver. After injection of heparin the metabolism of triglyceride-rich lipoproteins is initially accelerated, presumably as a result of the high levels of circulating LPL. Then follows a phase when lipoprotein metabolism is slower than normal, perhaps because endothelial LPL has been depleted by accelerated transport to and degradation in the liver.
Isolation and Characterization of Ryudocan and Syndecan Heparan Sulfate Proteoglycans, Core Proteins, and cDNAs from a Rat Endothelial Cell Line
Authors: Shworak Nicholas W. , Kojima Tetsuhito , Rosenberg Robert D.
Published: April 2009

We have isolated heparan sulfate proteoglycans (HSPGs) from cloned rat microvascular endothelial cells using a combination of ion-exchange chromatography, affinity fractionation with antithrombin III (AT III), and gel filtration in denaturing solvents. The anticoagulantly active heparan sulfate proteoglycans (HSPGact) which bind tightly to AT III bear mainly anticoagulantly active heparan sulfate (HSact) whereas the anticoagulantly inactive heparan sulfate proteoglycans (HSPGinact) possess mainly anticoagulantly inactive heparan sulfate (HSinact). The core proteins of HSPGact and HSPGinact were isolated by treatment with Flavobacterium heparitinase and purification by ion-exchange chromatography. SDS-PAGE showed that both sets of core proteins exhibited three major components with Mr of 25-, 30-, and 50-kD, respectively. Peptide mapping revealed that HSPG act and HSPGinact possess extremely similar core proteins. The primary sequences of internal peptides obtained from HSPGinact core proteins and the NH2-terminal sequence analyses of the 25-kD component from the HSPGinact core proteins demonstrate that the 30-kD component is a previously unidentified species – designated as ryudocan – with the 25-kD component representing a proteolytic degradation product; while the 50-kD component is the rat homolog of syndecan [Saunders S, Jalkanen M, O’Farrell S, Bernfield M: J Cell Biol 1989; 108:1547-1556]. Specific oligonucleotide probes were obtained for ryudocan and syndecan by PCR, and the corresponding cDNAs were isolated from a RFP-EC library. The cDNAs encode type I integral membrane proteins of 202 and 313 amino acids, respectively, which have homologous transmembrane and intracellular domains but very distinct extracellular regions. In particular, ryudocan exhibits only 3 potential glycosaminoglycan (GAG) attachment sites within the extracellular region while syndecan has 5 GAG attachment sites within the same domain. The levels of ryudocan and syndecan mRNA were measured by quantitative PCR in primary microvascular endothelial cells and associated non-endothelial cells isolated by cell sorting. Ryudocan and syndecan mRNAs were abundantly expressed in both populations representing about 0.1-0.5% of mRNA.
Mechanisms of Inhibition by Heparin of Vascular Smooth Muscle Cell Proliferation and Migration
Authors: Au Tina , Kenagy Richard D. , Clowes Monika M. , Clowes Alexander W.
Published: April 2009

Heparin, an inhibitor of vascular smooth muscle cell proliferation and migration, affects a number of other cell functions. These effects include inhibition of growth factor binding, deposition of matrix proteins and gene expression. Various mechanisms have been proposed and, yet, how heparin works as an inhibitor remains unclear. We have postulated that heparin inhibits smooth muscle cell growth and migration by suppressing the expression of matrix-degrading enzymes such as plasminogen activators and interstitial collagenase. The molecular mechanism of heparin’s inhibitory action on these proteases is currently under investigation.
Structure-Function Relationships of the Thrombin-Thrombomodulin Interaction
Authors: Sadler Evan , Lentz Steven R. , Sheehan John P. , Tsiang Manuel , Wu Qingyu
Published: April 2009

Thrombomodulin is an anticoagulant protein cofactor that modulates the substrate specificity of thrombin and promotes the cleavage of protein C. The structure-function relationships of the thrombin-thrombomodulin interaction have been explored by recombinant DNA and protein chemistry methods. Thrombomodulin binds to thrombin at an anion-binding exo-site on the carboxyl-terminal side of the substrate binding cleft. This interaction interferes with the recognition and cleavage of fibrinogen, factor V, and the platelet thrombin receptor. Binding to thrombomodulin also protects thrombin from inhibition by heparin cofactor II. The major thrombin binding site on thrombomodulin consists of EGF-like domains 5 and 6. In addition, EGF-like domain 4 is required for thrombomodulin to accelerate the activation of protein C. Some thrombomodulin molecules contain a chondroitin sulfate moiety attached to a Ser/Thr-rich domain adjacent to the cell membrane. This modification is not required for the cofactor activity of thrombomodulin, but appears to contribute to ‘direct anticoagulant’ activity – the ability of thrombomodulin to inhibit fibrinogen clotting, factor V activation, and platelet activation. The chondroitin sulfate moiety of thrombomodulin also can affect the rate of thrombin inhibition by antithrombin III, possibly by competing with heparin for the heparin binding site on thrombin. Detailed understanding of these interactions could lead to new strategies for the treatment of bleeding or thrombotic disorders.
Modulation of Vascular Antithrombin III in Human Cardiac Allografts
Authors: Faulk Page , Labarrere Carlos A.
Published: April 2009

The natural anticoagulant pathway involving heparan sulfate proteoglycan and antithrombin III (ATIII) was studied in serial biopsies from 90 cardiac allograft recipients. The ATIII component of this pathway was identified immunocytochemically on venous endothelium and arterial smooth muscle cells and intima of normal donor hearts and stable allografts. Unstable grafts lacked vascular ATIII and contained fibrin deposits. Neither stable nor unstable grafts had ATIII-reactive capillary endothelium. Grafts with absent vascular ATIII could (1) result in death, (2) revert to an arterial/venous ATIII distribution or (3) develop ATIII-reactive capillary endothelium. The development of ATIII-reactive capillaries was associated with a survival advantage, and such reactivity seemed to be promoted by heparin.
Heparin and Pregnancy in Women with a History of Repeated Miscarriages
Authors: Mclntyre John A. , Taylor Colin G. , Torry Donald S. , Wagenknecht Dawn R. , Wilson Jane , Faulk Page
Published: April 2009

Many patients who experience recurrent spontaneous abortions (RSA) have high titered antibodies to trophoblast antigens and/or negatively charged phospholipids. Pregnancy success has been documented in some of these patients subsequent to heparin treatment. The effect of heparin on in vitro assays used to detect antibodies to phospholipids and trophoblast antigens has been investigated. We have found that complement-mediated detection of antibodies to trophoblast and lymphocyte antigens is inhibited by absorption of sera with solid-phase heparin. The data show that such inhibition involves an inhibitor and a heparin-sensitive regulator of the inhibitor. Heparin inhibits binding of antiphospholipid antibodies to phospholipids in solid-phase ELISA. The mechanism for this inhibition appears to involve an interaction between heparin and antibody to phospholipid. These findings reveal novel heparin-mediated reactions that bridge immunological and hematological interactions. The extent of heparin modulation of these antibody reactivities should be clarified in future clinical trials involving heparin treatment for RSA.
Interactions of Heparins in the Vascular Environment
Authors: Dawes Joan
Published: April 2009

Heparins are exposed in vivo to a complex environment containing heparin-binding proteins in solution, on the surface of cells and in the extracellular matrix. However, most studies of heparin binding have been carried out in simplified systems which fail to address the competition for binding resulting both from the different concentrations of constitutent proteins and their relative affinities for heparin. In the blood heparin binds to platelets in a saturable, specific and reversible interaction which occurs in the presence of competing plasma proteins and which may be prothrombotic. Similar binding to monocytes and endothelial cells occurs but has not yet been confirmed in whole blood. Such interactions could inhibit coagulation resulting from generation of tissue factor activity and modulate endothelial responses which affect coagulation, fibrinolysis and cell growth as well as representing a physiologically significant anti-inflammatory function of heparin. Low-molecular-weight (LMW) heparins have lower affinities than unfractionated heparin for all cell receptors studied and are less likely to exert their effects through cellular interactions. In whole plasma in the absence of platelet release, antithrombin III was the most abundant protein bound to therapeutic doses of unfractionated heparin, and histidine-rich glycoprotein its only effective competitor, while both histidine-rich glycoprotein and vitronectin were potentially important modulators of LMW heparin activity. Sequestration of vitronectin and complement factor H by immobilised heparins could promote an effective defence against complement-mediated prothrombotic activity and cell damage under physiological conditions. In addition, the ability of immobilised heparin to bind fibronectin, vitronectin and fibrinogen in a plasma milieu may increase the exposure of these adhesive ligands and stimulate interaction with activated platelets through the αIIb/β3-integrin.
Diagnostic Strategies in Acute Pulmonary Embolism
Authors: Nyman Ulf
Published: April 2009

A firm diagnosis of pulmonary embolism (PE) to prevent over- or undertreatment requires an integrated use of ventilation-perfusion lung scintigraphy (V/Q scan), a recent chest X-ray, bilateral selective pulmonary angiography and venous studies. The V/Q scan should be reported in terms of probabilities according to defined criteria and be combined with clinical probabilities before a treatment decision is made. A negative V/Q scan, a low-probability scan combined with low clinical suspicion or a high-probability scan with a high clinical suspicion is generally conclusive. Patients with intermediate (indeterminate) scan probability or with discordant scinti-graphic clinical probability need further work-up with pulmonary angiogram or venous studies. If neither scintigraphy nor pulmonary angiography is available, accurate venous studies of the lower legs may guide treatment decision in patients suspected of having PE. We need more research to define if all patients with PE but only a minor or no clot burden proven by venous studies really need treatment.
Partial Reconstitution of Cutaneous Microvessels in Long-Term Survivors after Allogeneic Bone Marrow Transplantation
Authors: Haeusermann P. , Kump E. , Rovó A. , Tichelli A. , Itin P. , Gratwohl A. , Biedermann B.C.
Published: April 2009

Background: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) and skin is involved in acute and chronic disease. Immune-mediated vessel attack and subsequent microvessel loss have been observed in skin of patients with chronic GVHD. Objectives: To test whether long-term survivors (LTS) after allogeneic HSCT without cutaneous GVHD show signs of persistent vascular remodeling. Methods: Microvessels in skin biopsies were investigated in a cohort of 32 LTS with a median follow-up of 17 years (range 11–26). Five were currently classified as having chronic GVHD other than skin involvement. Results: LTS showed no significant difference in median microvessel density and relative vessel size distribution pattern compared to healthy controls. Past experience of GVHD and current status of chronic GVHD other than skin involvement had no impact on vessel density. In contrast, recipients with chronic cutaneous GVHD of sclerotic type and patients with lichen sclerosus have significant microvessel loss in the upper dermis. Conclusion: The complex therapy of allogeneic HSCT had no sustained effect on the microvascular architecture of LTS when clinicopathological evidence of cutaneous GVHD is absent. Microvascular remodeling as observed during chronic GVHD recovers completely after resolution of chronic cutaneous GVHD.
Thrombolysis for Acute Myocardial Infarction
Authors: Van de Werf Frans
Published: April 2009

Thrombolysis has become standard treatment in the great majority of patients with an acute transmural myocardial infarction. Large placebo-controlled trials have shown that thrombolytic therapy, when given within 6 hours after onset of symptoms, reduces infarct size, preserves left ventricular function and improves survival [1-6]. Because of discrepancies observed between the effects of thrombolysis on left ventricular function and survival [7] and since beneficial effects have also been observed in subgroups of patients treated after 6 hours [4], additional mechanisms of actions (besides salvage of ischemic myocardium) have been supposed: limitation of infarct expansion and left ventricular remodeling, increased electrical stability and provision of collaterals to other myocardial regions. The equal clinical outcome with different agents, in spite of proven differences in efficacy for early recanalization, in GISSI-2/ International [8] and ISIS-3 [9] has further challenged the importance of the original pathophysiological mechanism (early reperfusion and myocardial salvage). The results of recent megatrials (GUSTO [10], EMERAS [11] and LATE [12]) and of a recent meta-analysis (FTT’s collaborative Study Group) [13] have resolved many uncertainties. The implications of these recent trials for the selection of both patients and thrombolytic strategies and for the future development of new treatment can not be overestimated.
Molecular Genetics Aspects of Factor XI Deficiency and Glanzmann Thrombasthenia
Authors: Seligsohn Uri , Peretz Hava
Published: April 2009

Factor XI deficiency and Glanzmann thrombasthenia are among the hereditary disorders frequently encountered in Israel. Factor XI deficiency is particularly frequent in Ashkenazi (Euorpean) Jews with 1:190 individuals affected by the severe deficiency and 8.1% of the population being heterozygotes. So far 4 mutations causing factor XI deficiency have been identified of which the type II (a non-sense mutation) and type III (a missense mutation) are predominant and type I and IV observed only in 5 families. Recently, the type II mutation was observed in Iraqui-Jews as well with 3.7% of 400 unrelated subjects being heterozygotes and with the type III mutation completely absent. Since Iraqui-Jews represent the original gene pool of Jews who lived in Babylon 2500 years ago we hypothesize that the type II mutation is ancient and that the type III mutation occured more recently, after the divergence of the original Babylonian Jews into Ashkenazi, Sephardic (Spanish) and Middle Eastern Jews. Preliminary data on factor XI intragenic polymorphic markers indeed indicate that type II and type III mutations reside on chromosomes each characterized by a different specific haplotype. Fifty living patients with type I Glanzmann thrombasthenia (28 families) have been observed in Israel. Most of them are Iraqui-Jewish and the rest are Arabs (5 families) and one Iranian Jewish. All Iraqui-Jewish patients have an IIbp deletion within exon 12 of the glyco-protein (GP) Ilia resulting in a shift of the reading frame that leads to premature termination of the GPIIIa synthesis. In 3 of the Arab families a 13bp deletion was found in exon 4 of the GPIIb gene causing forced alternative splicing with 6 amino acids missing at the N-terminal region of GPIIb. For the detection of both mutations simple PCR methods were devised enabling carrier detection and prenatal diagnosis by CVS.
Venous Thrombosis Today
Authors: Kakkar V.V.
Published: April 2009

Over the last 25 years, considerable progress has been made in the prevention, diagnosis and therapy of venous thromboembolism. The epidemiology of the disease has been investigated, defining patient groups at risk. Safe and effective methods of venous thrombosis prophylaxis have been evaluated in a wide range of patient populations, and recommendations for their application have been widely disseminated. Non-invasive techniques for the diagnosis of venous thrombosis and pulmonary embolism have been developed, and their capabilities and limitations have been defined. Guidelines for existing therapy have been refined, and new therapeutic agents have been introduced into clinical practice. A brief review of these is presented.
Antithrombotic Drugs in Peripheral Obliterative Arterial Diseases
Authors: Coccheri S. , Palareti G. , Fortunato G.
Published: April 2009

In the natural history of patients with peripheral obliterative arterial disease (POAD) the prognosis of the complaint “intermittent claudication” is relatively good and the amputation rate is presently only about 3%. However, POAD patients carry a high risk of cardiovascular events and their cumultative mortality rate within 10 years is as high as 40-50%. Atherothrombotic events in the coronary and, less frequently, cerebral arteries are by far the first cause of death and disability in these patients. The rationale for antithrombotic drugs in the treatment of POAD lies in the pivotal role of platelet activation and thrombin formation in the evolution of the atherothrombotic lesions, but also in the effect of some of these drugs on the regulation of microcirculatory responses. In acute thrombotic arterial occlusion, Heparin is the “first application” drug, especially in support of interventional revascularisation procedures. Regional thrombolysis often coupled with angioplasty (PTA), or systemic thrombolysis, are effective in revascularisation of especially infrainguinal-supra popliteal occlusions. However, controlled clinical trials are needed. In chronic POAD, intermittent claudication can be improved with a rational walking exercise programme, but, besides pentoxyphilline, especially ticlopidine significantly adds to the benefits of exercise. Regarding districtual progression of atherothrombosis and especially cardiovascular events, both aspirin and ticlopidine have been shown effective in single studies or meta-analyses. In a recent observational study of pooled data the cumulative endpoint including myocardial infarction, stroke and vascular death was reduced by 25 ± 10% in the generality of patients treated with anti-platelet drugs. Finally, in critical limbs ischemia (CLI), some prostanoid compounds as Iloprost and Prostaglandin El favourably influence rest pain and ulcer healing, but less evidence is available on their effects on hard events as amputation and death. In conclusion, following the general indication to “be conservative” in the treatment of these patients, it seems clear that antithrombotic drugs have become by far a key medication in all different phases of POAD.
Cancer and Thrombosis
Authors: Donati Maria Benedetta
Published: April 2009

Thrombosis is the most frequent complication and the second cause of death in patients with overt malignant disease. Increasing evidence suggests that thrombotic episodes may also precede the diagnosis of cancer by months or years thus representing a potential marker for occult malignancy. Recently, emphasis has been given to the potential risk of cancer therapy (both surgery and chemotherapy) in enhancing the risk for thromboembolic disease. Post-operative deep vein thrombosis is indeed more frequent in patients operated for malignant diseases than for other disorders. On the other hand, both chemotherapy and hormone therapy are associated with an increased thrombotic risk, which can be prevented by low-dose oral anticoagulation. Possible contributory causes for thromboembolic disease in cancer include the capacity of tumor cells and their products to interact with platelets, clotting and fibrinolytic systems, as well as their interactions with endothelial cells and tumor-associated macrophages. Cytokine release, acute phase reaction and neovascularization may contribute, in cancer patient, to in vivo clotting activation, which is well documented by several plasmatic markers of an hypercoagulable state. Last but not least, a direct pathogenetic role of clotting activation in the progression of malignancy has been repeatedly proposed on the basis of pharmacological studies with anticoagulant/fibrinolytic drugs in experimental animals and selected clinical malignancies, as well as, lately, in genetically modified animal models (e.g. mice transgenic for PAI-1).
Inflammatory Mediators and Their Influence on Haemostasis
Authors: Salgado A. , Bóveda J.L. , Monasterio J. , Segura R.M. , Mourelle M. , Gómez-Jiménez J. , Peracaula R.
Published: April 2009

Sepsis is the most important cause of mortality in the Intesive Care Units. At present, sepsis is understood to be the inflammatory response of the host to infection, rather than a direct effect of microbial aggression. From the clinical standpoint, this inflammatory response is known as systemic inflammatory response syndrome (SIRS). Pathophysiologically, SIRS is characterized by the activation of several groups of cell (monocytes/macrophages, PMNs, and endo-thelial cells) and by the release of inflammatory mediators (cytokines and others). Tumor necrosis factor (TNF) is the first cytokine released by endotoxin action over monocyte/macrophage. TNF secretion, modulated by interferon gamma (IFNγ) and interleukin 10 (IL-10), is followed by release of other cytokines such as interleukins (IL) (IL-1, IL-6 and IL-8). These mediators are able to act over hemostasis activating the extrinsic pathway through tissue factor expression. The action of the mediators over endothelial cells induces an increase in plasminogen activator inhibitor type 1 (PAI-1) levels with inhibition of fibrinolysis. Both coagulation activation and fibrinolysis blockage result in fibrin deposit in the microvascular system. The complexity of the mechanisms implicated in systemic inflammatory response make a general rule so difficult to establish, because patient response is highly individualized and it is not possible to know which moment of this dynamic process is being analyzed.
New Diagnostic Strategies for Lupus Anticoagulants and Antiphospholipid Antibodies
Authors: Triplett Douglas A.
Published: April 2009

Laboratories are currently challenged with the problem of ruling out APA in a patient plasmas. In order to optimize the identification of these antibodies, it is necessary to institute a well-planned approach. Both coagulation assays for the identification of LA and solid phase ELISA assays for the identification of ACA are indicated. In the case of LA, it is often necessary to screen the patient plasma with more than one test system. If two screening tests are negative, no further evaluation for the presence of LA is indicated. However, it is imperative to also perform ACA testing. The literature describing LA and ACA testing is growing exponentially. Several new integrated test systems which seek to simplify the approach to the diagnosis of LA have been introduced. These systems employ one test performed under two different conditions (low and high PL concentration). This approach may prove to be the most cost-efficient way of establishing the diagnosis of LA.