bluuebunny/crossref_metadata_2025 huggingface dataset:
Von Willebrand Factor Antigen and Factor XI Activity Levels As Predictors of Bleeding Tendency in Israeli Patients with Von Willebrand's Disease
Authors: Brenner Benjamin , Stemberg Tamar , Laor Arieh , Tavori Shulamit , Tatarsky Ilana , Lanir Naomi
Published: November 2007

Previous preliminary data and case reports have suggested an association of von Willebrand's disease (vWD) with factor XI deficiency and platelet abnormalities. We have analyzed the prevalence of factor XI deficiency and thrombocytopathy in a cohort of Israeli patients with vWD. Decreased factor XI levels (<67 U/dl) were documented in 35 of 63 (36%) vWD subjects; factor XI levels were <30 U/dl in five of 60 (8%). A significant decline in ADP-induced platelet aggregation (<30% of control) was found in 48% of vWD patients. Likewise, epinephrine-induced aggregation was reduced in 41%, and collagen-induced aggregation was decreased in 7% of vWD patients. Logistic regression analysis showed that while Ivy bleeding time, ristocetin cofactor, and ristocetin-induced platelet aggregation did not predict bleeding, both von Willebrand factor antigen and factor XI activity levels predict bleeding in patients with vWD. These findings suggest that mild factor XI deficiency and thrombocytopathy are common in Israeli subjects with vWD and that associated factor XI deficiency can result in clinical bleeding in these patients. Key Words: Von Willebrand' s disease—Factor XI deficiency—Thrombocytopathy.
Orally Ingested Heparin Is Absorbed in, Humans
Authors: Engelberg Hyman
Published: November 2007

It has been accepted for many years that orally ingested heparin is not absorbed. Recent evidence has shown that heparin placed in the stomach of rats is very rapidly absorbed and that it also quickly and almost completely attaches to the vascular endothelium and prevents jugular vein thrombosis. Within 6 min, heparin was undetectable in the blood plasma. If a similar situation exists in humans, blood samples taken >15 min after heparin ingestion will lack evidence of anticoagulant activity. In this study, 45 individuals swallowed 20,000 units of heparin. Plasma activated partial thromboplastin time (APTT) levels were determined (in duplicate) before and at frequent intervals for 30 min after the heparin ingestion. There as a slightly prolonged APTT (range, 1-5 s) after swallowing the heparin. The average increase in the APTT was 2.3 s, which is statistically significant (p < 0.001), as the standard deviation of the method is .43 s. In several instances, frozen plasma aliquots, analyzed for heparin by a chromogenic method, showed its presence after ingestion. The preliminary results are important, although obviously oral heparin does not attain effective anticoagulant levels, as the many non-anticoagulant actions of heparin and the observation of its absorption after oral ingestion present numerous possibilities for new clinical applications. Key Words: Heparin—Oral absorption.
Fetal Wastage Syndrome due to Blood Protein/Platelet Defects: Results of Prevalence Studies and Treatment Outcome with Low-Dose Heparin and Low-Dose Aspirin
Authors: Bick Rodger L. , Laughlin H. Robert , Cohen Brian M. , Staub A. Jay , Madden James , Toofanian Ali
Published: November 2007

Fetal wastage syndrome is characterized by recurrent spontaneous abortion. Many syndromes are associated with recurrent fetal loss, including anatomical anomalies, endocrine/hormonal abnormalities, and coagulation defects, with coagulation defects accounting for ∼30% of cases. Most procoagulant factor defects are due to inadequate fibrin-mediated implantation of the fertilized ovum into the decidua. However, blood protein/ platelet defects leading to hypercoagulability and thrombosis are associated with thrombosis of placental vessels, precluding viability of the implanted ovum or later fetus. During the past 2 years, we have seen 46 patients with fetal wastage syndrome due to thrombosis-associated hemostasis defects. In this group, there have been three patients with sticky platelet syndrome, one patient with dysfibrinogenemia, four patients with congenital protein S deficiency, 35 patients with anticardiolipin antibodies, and one patient with a lupus anticoagulant. Patients were started on one low-dose aspirin (ASA), 81 mg per day preconception, at time of diagnosis, and low-dose s.c. porcine heparin at 5,000 units every 12 h was added immediately postconception. The combination of low-dose ASA plus low-dose s.c. porcine heparin was used throughout pregnancy. All patients achieving pregnancy have had uneventful, normal deliveries. It appears that blood protein/platelet defects leading to thrombosis and associated with recurrent fetal loss can be successfully managed with the use of preconception low-dose ASA, followed by immediate postconception addition of fixed low-dose porcine heparin, both used throughout pregnancy. Using this regimen, our success rate has been 100%. Ideal heparin doses, which might be much lower than our empirically chosen and currently used doses, remain to be defined in this particular indication. Key Words: Fetal wastage syndrome—Heparin—Aspirin.
Platelet Function in Alcoholics Treated with Disulfiram
Authors: Randi Maria Luigia , Zanella Ilia , Pujatti Piero , Soini Barbara , Girolami Antonio
Published: November 2007

Disulfiram is usually used in alcoholics as aversion therapy. It binds to various enzymes and pro teins in blood and in tissues. In particular, it inhibits the thromboxane synthetase in human platelets and, for this reason, it has been surmised that disulfiram has a possible effect on platelet function. So far, disulfiram failed to confirm this hypothesis in healthy volunteers. However, it appears able to decrease the threshold collagen concen tration for platelet aggregation. Our aim was to evaluate the effect of disulfiram on the platelet function of alco holics. In this study, 24 alcoholics, divided in group A (12 abstinent patients with disulfiram 200 mg/day), group B (12 abstinent patients without treatment), and 17 normal controls, are reported. Different tests were performed at time 0 (acute alcohol intoxication), time 2, and time 15 after the beginning of abstinence. A significant increase was observed in bleeding time (BT) of group B and in platelet count of both groups. No modification was seen in prothrombin time. In group A, a significant increase of platelet aggregation under adenosine diphosphate (ADP; 2 μ M) stimulus was observed. Whereas no difference was seen in platelet 5-hydroxytryptamine (5-HT), serum 5-HT increased significantly at time 15 in group A. We con clude that the increase in serum 5-HT was probably due to the inhibition of monoamine oxidase (MAO) promoted by disulfiram, followed by an activation of MAO induced by disulfiram.
State-of-the-Art Review : Monitoring of High-Dose Intravenous Heparin Therapy—A Contribution to the Safety of Heparin Monitoring
Authors: Haushofer Alexander , Halbmayer Walter Michael , Radek Johannes , Fischer Michael
Published: November 2007

Whenever unfractionated heparin (UFH) is administered i.v. in therapeutic doses, therapeutic drug monitoring of the anticoagulant response should be man datory and the dose should be adjusted accordingly. UFH therapy is usually monitored by the activated partial thromboplastin time (APTT). A 1.5- to 2.5-fold prolonga tion of APTT has become generally accepted as an indi cator of effective i.v. anticoagulation, but it has become common to recommend this ratio without testing the APTT reagents used for their heparin sensitivity and for their actual therapeutic APTT ratio (actual APTT: normal control APTT). Internal heparin sensitivity testing of APTT reagents is managed using heparin sensitivity curves obtained from heparin-spiked normal plasma pool. The most common APTT reagents in Austria and a newly developed double activated APTT reagent were tested for their heparin sensitivity and therapeutic ratios on differ ent automated analyzers, depending on their optical and chemical conditions. Also, newly developed, commer cially prepared heparin standards (0.19, 0.52, 0.86 IU heparin/ml plasma) were tested. APTT reagents differ in their heparin sensitivity and therapeutic ratio; variations in heparin sensitivity are also seen between different an alyzers. Therefore, therapeutic ratio should regularly be checked and the literature should always state which APTT reagent was used on which instrument.
Familial Thrombophilia: A Review Analysis
Authors: van den Belt Angelique G. M. , Prins Martin H. , Huisman Menno V. , Hirsh Jack
Published: November 2007

The correct approach to the management of the asymptomatic carrier with a recognized inherited thrombophilic disorder is uncertain because reliable in formation of the risk of spontaneous (unprovoked) throm bosis in these disorders is not available. To determine the best available estimate of the annual incidence of spon taneous thrombosis in asymptomatic carriers of disorders that have been linked to familial thrombophilia, we per formed a literature review. Using Medline search from 1965 to 1992, supplemented by manual searches, we re trieved all articles that presented data on antithrombin III, protein C, protein S, dysfibrinogenemia, plasmino gen, histidine-rich glycoprotein, heparin cofactor II, and fibrinolysis in relation to thrombosis. Publications were included in the analysis if they (1) reported one or more probands with thrombotic disease and a heterozygous biochemical abnormality of the hemostatic system, (2) assessed the presence of this abnormality in family mem bers independent of the presence or absence of a history of thrombotic disease, and (3) assessed the presence of a history of thrombotic disease in all available family mem bers. The biochemical status and clinical details of all family members reported were extracted from each eligi ble article. For each abnormality the odds ratio for throm bosis was compared in family members with and without the biochemical abnormality. If applicable, thrombosis- free survival and age-specific incidences of thrombosis were calculated. The thrombotic episodes were classified as spontaneous or secondary to a recognized risk factor, and the proportion of spontaneous episodes was calcu lated. The influence of diagnostic suspicion bias in symp tomatic patients with a family history of thrombosis was reduced by recalculating the absolute incidence of throm bosis from the odds ratio after adjusting the incidence of venous thrombosis in nonaffected family members to that observed in the general population. Statistically signifi cant associations between the presence of a biochemical abnormality and a history of venous thrombosis were found for antithrombin III deficiency types 1 and 2a and 2b, protein C deficiency type 1, and protein S deficiency type I. Dysfibronogenemia was statistically significantly associated with venous as well as arterial thrombosis. Thirty-five to 67% of the events were classified as being provoked, as they occurred following exposure to a rec ognized risk factor for thrombosis. The recalculated an nual incidence of spontaneous thrombosis was 0.6 to 1.6%/year. It is concluded that this relatively low inci dence does not warrant life-long continuous use of anti coagulant prophylaxis since the reported risk of major and fatal bleeding associated with the use of oral antico agulants is 2-3 and 0.4%/year, respectively.
aPTT in Heparinized Plasma: Influence of Reagent, Acute-Phase Reaction, and Interval Between Sampling and Testing
Authors: Strekerud Finn G. , Abildgaard Ulrich
Published: November 2007

Plasma samples from 10 healthy persons and 10 patients with acute-phase reaction were heparinized in vitro to obtain 0.00-0.70 U/ml. The activated partial thromboplastin time (aPTT) was then determined, using an optical method (Automated Coagulation Laboratory) and four reagents (actin, Cephotest, Platelin, and Throm bosil). The heparin sensitivity showed variation between individuals and was lower in acute-phase plasma than in normal plasma. There was also a marked difference in heparin sensitivity among the different reagents; actin was the least sensitive reagent, while Platelin was the most sensitive reagent in normal plasma and Thrombosil the most heparin-sensitive reagent in acute-phase plasma. Delay in testing prolonged the aPTT values in both acute- phase and normal heparinized plasma. With actin and Ce photest, a delay of 90 min at 22°C resulted in 30-50% prolongation of the aPTT. A delay of 150 min caused a prolongation of 75-110% with actin. Cephotest, Platelin, and Thrombosil were less prolonged. Ex vivo samples from heparinized plasma showed similar degrees of pro longation. Storage at 4°C resulted in less prolongation. Assuming a therapeutic range of 0.35-0.70 U/ml of hep arin, the therapeutic aPTT ratio ranges in heparinized, acute-phase plasma were 1.5-3.0 for actin and 2.5-4.5 for Cephotest, Platelin, and Thrombosil. These results un derscore certain limitations in monitoring heparin therapy with the aPTT system. Unless the assay is performed within 30 min after sampling, unduly prolonged aPTT val ues will be recorded. This may lead to underdosing of the patient.
Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes
Authors: Jackson Charles V. , Satterwhite Julie , Roberts Eiry
Published: November 2007

Efegatran (LY294468), a tripeptide arginal in hibitor of the catalytic site of thrombin, is being devel oped as a parenteral anticoagulant for the treatment of acute coronary syndromes. Efegatran was studied in a canine model of coronary artery thrombosis to determine its ability to prevent thrombus formation and as an ad junctive anticoagulant to thrombolysis, in phase I clinical studies, and phase II clinical studies in unstable angina. In the preclinical in vivo studies in dogs, efegatran pro duced a dose-dependent increase in clotting times and demonstrated a selectivity for thrombin time (TT) changes. The activated partial thromboplastin time (APTT)-TT ratio (that is, based on the dose to double each clotting time) determined in dogs from ex vivo blood samples was 8: 1. This observation was similar to that obtained during the phase I studies in normal volunteers where the APTT-TT ratio was 12:1. The canine and hu man clotting systems responded similarly at doses of efe gatran where comparisons could be made (0.25-1.0 mg/ kg/h). The kinetics of the anticoagulant activity of efega tran in dogs and humans were linear and nonsaturable over the dose ranges studied. Efegatran was also found to be an effective adjunctive anticoagulant during streptoki nase-induced thrombolysis in dogs, preventing reocclu sion without increasing bleeding risk. The novel an tithrombin, efegatran, has demonstrated dose-dependent and safe anticoagulation in animal and human studies. Efegatran is presently undergoing phase II clinical studies in unstable angina and acute myocardial infarction pa tients.
State-of-the-Art Review: Activated Protein C Resistance: Clinical Implications
Authors: Zöller Bengt , Hillarp Andreas , Dahlbäck Björn
Published: November 2007

The discovery of inherited resistance to activated protein C (APC) as a major risk factor for venous thrombosis has dramatically improved our understanding of the pathogenesis of venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene (FV) that results in substitution of arginine, R, at position 506 by glutamine, Q. (FV:Q506). The mutation renders factor Va partially resistant to degradation by APC. A functional APC resistance test, which includes predilution of the patient plasma with factor V-deficient plasma, is found to be 100% sensitive and specific for the presence of FV:Q506 and is useful as a screening assay. Carriers of the FV:Q506 allele have increased thrombin generation, resulting in hypercoagulability and a lifelong increased risk of venous thrombosis. In Western countries, APC resistance due to the FV mutation is present in 20-60% of thrombosis patients and in 1-15% of healthy controls, whereas the mutation is virtually absent from ethnic groups other than Caucasians. This may explain the high incidence of venous thrombosis in Western countries. The thrombotic risk in APC-resistant individuals may be further increased by other genetic defects, e.g., protein C or protein S deficiency, and by exposure to circumstantial risk factors, e.g., oral contraceptives, pregnancy, immobilization, and surgery. The question is thus raised as to whether general screening for APC resistance before circumstantial risk factors occur is warranted in Western countries. Key Words: Factor V—APC resistance-Protein C-Protein S—Thrombosis—Mutation.
Two Methods for Intraplatelet Serotonin Evaluation: Their Use in Thrombocytosis
Authors: Zerbinati Patrizia , Luigia Randi Maria , Rossi Carla , Soini Barbara , Girolami Antonio
Published: November 2007

The content of platelet dense bodies is considered to be decreased in thrombocytosis associated myeloproliferative disorders and normal in reactive thrombocytosis. Intraplatelet serotonin i.e., 5-hydroxytryptamine (5HT), content is usually considered a particularly good marker. We report our experience of platelet 5HT levels evaluated by radioimmunoassay (RIA) and fluorimetric assays in patients with high platelet counts due to essential thrombocythemia (48 patients) or reactive thrombocytosis (34 patients). The diagnosis of essential thrombocythemia was made according to Polycythemia Vera Study Group criteria. A significant statistical difference was observed in serotonin platelet content between essential thrombocythemia and secondary thrombocytosis patients both with fluorimetric and RIA assays. On the contrary, no difference was evident between reactive thrombocytosis patients and normal control subjects. However, a significant difference was observed between 5HT in serum and platelet pellets when evaluated by RIA. Statistical analysis with the X2 test showed that the sensitivity of the fluorimetric assay is slightly higher than that of the RIA assay; however, specificity is about the same with the two methods. It is possible that the two assays measure different molecules. At any rate, the fluorimetric assay seems to be better in evaluating the platelet content of 5HT at least in patients with high platelet counts. Key Words: Thrombocytosis—Serotonin.
Antiphospholipid Antibodies Do Not Seem to Be Associated With Deep Vein Thrombosis: A Case Control Study
Authors: Zanon Ezio , Simioni Paolo , Saracino Maria A. , Prandoni Paolo , Girolami Bruno , Sardella Corrado , Girolami Antonio
Published: November 2007

Antiphospholipid antibodies (APAs) are associated with venous thromboembolism in patients with systemic lupus erythematosus (SLE). In patients without SLE, but with deep vein thrombosis (DVT) this association is established only for patients with lupus anticoagulant (LA). In a case-controlled study APAs were determined in 171 consecutive outpatients who underwent phlebography at the first episode of clinically suspected DVT of lower limbs. Phlebography confirmed the presence of DVT in 54 (32%) patients and excluded it in 117. Antiphospholipid antibodies (exluding LA) were detected in 5 (9.2%) of the 54 patients with DVT and in 7 (5.9%) of the 117 subjects without DVT, The prevalence of APAs tended to be higher in patients with DVT than in patients without DVT, but the difference was not statistically significant (p = 0.3%). Antiphospholipid antibodies in the absence of LA are not associated with DVT in symptomatic patients. Therefore future studies should be performed before changing our clinical approach in APA-A positive but LA-negative patients. Key Words: Antiphospholipid antibodies-Deep vein thrombosis.
Evaluation of Whole-Blood Lumiaggregation
Authors: Podczasy John J. , Lee James , Vucenik Ivana
Published: November 2007

An evaluation of whole-blood lumiaggregation was conducted in a normal population. Platelet aggregation and adenosine triphosphate (ATP) secretion were monitored in a three-phase study that analyzed sample dilution, agonist dose response, and method comparison. In the first phase, the blood:saline ratio was varied; in the second phase, the concentration of the agonists was varied ; and in the last phase, a comparison of impedance aggregation and ATP release in whole blood to optical aggregation and ATP release in platelet-rich plasma (PRP) was performed. Five common platelet agonists— collagen, adenosine diphosphate (ADP), arachidonic acid, thrombin, and ristocetin—were used in this evaluation of the lumiaggregometer (Chrono-Log Corp., Havertown, PA, U.S.A.). The data revealed that the optimum blood:saline ratio for conducting platelet antigen studies is 1:1, although with some agonists other dilutions can be used. The agonist dose-response phase basically confirmed the manufacturer's concentration recommendations. Additionally, it was determined that platelet aggregation using the whole-blood impedance technique compared to the PRP optical method yielded similar information. Furthermore, the advantages of whole-blood impedance aggregation include its use in microsamples and more timely results due to minimal sample preparation. Key Words: Platelet aggregation—Lumiaggregation—Whole blood—Platelet-rich ptasma—ATP.
Heparin-Induced Thrombocytopenia: Prevalence in a Large Cohort of Patients and Confirmed Role of PF4/Heparin Complex as the Main Antigen for Antibodies
Authors: Fabris Fabrizio , Cordiano Immacolata , Salvan Federica , Saggin Leopoldo , Cella Giuseppe , Luzzatto Guido , Girolami Antonio
Published: November 2007

We performed a retrospective study on the prevalence of heparin-induced thrombocytopenia (HIT) in 233 patients receiving hog mucosa heparin therapy. Of these, 82 patients received s.c. calcium heparin, 130 patient received unfractionated (UF) i.v. heparin, and 21 patients received low molecular weight heparins (LMWH). An additional four patients, referred to our consultation and diagnosed by us as having clinically active type II HIT (HIT-II) were also studied. The mean platelet count of the 233 patients receiving heparin showed a significant decrease after 2 days of heparin treatment and a following significant increase 6 days later (basal: 257 ± 147 x 109 platelets/L; day 2: 239 ± 122, p < 0.0002; day 6: 286 ± 119, p < 0.004). Of the 212 patients receiving UF heparin, 13 (6%) fulfilled the criteria for HIT-II: seven of these had received i.v. heparin (mean daily dose 26,600 ± 4,082 IU ± SD) and six had received s.c. heparin (mean daily dose 21,428:t 6,900 IU). Their mean basal platelet count was 226 ± 100 SD × 109 platelets/L and the nadir during heparin treatment was 78 ± 39 x 10 9 platelets/L. Thrombotic complications occurred in four (30.7%) of the 13 patients with HIT-II. Since the immunological mechanism has been demonstrated for HIT-II and since platelet factor 4 (PF4) was identified as the co-factor for the binding of heparin-related antibodies, we set up our own enzyme-linked immunosorbent assay (ELISA) for testing antibodies against PF4/heparin complex bound through electrostatic bridges to the solid phase. The highest binding capacity of HIT-related IgG to the multimolecular complex was obtained at 20 μg/ml for PF4 and 3 μg/ml for heparin, corresponding to 250 ng of PF4 and 42 ng of heparin in each microtiter well. Such binding was inhibited in a dose-dependent manner by increasing amounts of heparin, protamine hydrochloride, and a monoclonal antibody anti-human PF4 clone 1OB2. We observed that HIT-related antibodies bound also to PF4/LMWH complexes but the optimal PF4/glycosaminoglycan ratio appeared more critical for LMWH (enoxaparin, fraxiparin, and pamaparin) than for UF heparin. Sera from eight patients with HIT-II were tested by PF4/heparin ELISA; six of these had IgG against the complex PF4/heparin and three also had IgM. The persistence of HIT-related antibodies was investigated in three patients: in one such antibodies were still detectable 3 years after the acute episode, while in the other two, they disappeared after 6 months and 1 year, respectively. Key Words: Heparin-related anti body—Platelet factor 4 (PF4)—Heparin—Low molecular weight heparin—Thrombocytopenia—Thrombosis.
Venous Thromboembolism in Heterozygotes for Factor V Leiden—The Second-Hit Hypothesis: A Report of Two Patients and a Review of the English-Language Literature
Authors: Pak Ho David , Perrotta Augustine L.
Published: November 2007

Resistance to activated protein C (factor V Leiden, FV-R506Q) is the most prevalent inherited hypercoagulable state with a frequency of 4.5% in the American population, but 70% of heterozygotes do not experience venous thromboembolic disease. Heterozygosity for FV-R506Q will coexist in patients with deficiencies of protein S (26.1 %), protein C (14.9%), antithrombin III (15.1%), homocystinuria/ hyperhomocysteinemia (29.6%), pregnancy or postpartum (27.9%), oral contraceptives (27.5%), trauma and surgery (18.6%), and lupus anticoagulant and/or antiphospholipid antibodies (40%). The second-hit hypothesis proposes that heterozygotes for factor V Leiden mutation who do experience venous thrombosis will have a second hypercoagulable state either hereditary or acquired. Key Words: Thromboembolism—Factor V Leiden—Heterozygotes.
The Role of Factor XIII and Elastase in Gastrointestinal Complications in Henoch-SchoenleinPurpura
Authors: Kröniger Amo , Schwerk Wolf-Burkhardt , Bierbrauer Axel V. , Seitz Rainer , Egbring Rudolf
Published: November 2007

Henoch-Schoenlein purpura (HSP) is a generalized anaphylactoid "teucocytoclastic" vasculitis, which in more than 50% of patients is complicated by gastrointestinal symptoms such as vomiting, abdominal pain, melena and life-threatening bleedings. In five consecutive patients with HSP on admission factor XIII (F XIII) was decreased to 8-58% of normal. In acute attacks an enormous F XIII consumption takes place. Recurrent release of elastase from inflammatory cells (PMNL, monocytes, macrophages) can be detected by intermittent peaks of elastase-α 1-protease inhibitor (ELP-α1-PI) complex in plasma (peak values 450-950 ng/mi). Elastase is considered to cause specific F XIII degradation with bleeding into the intestinal wall as a result. High-dose F XIII substitution therapy is effective in controlling bleeding complications and abdominal pain. The benefit of F XIII therapy could be demonstrated in a rapid and marked shrinking of the intramural hematomas by raltrascanic scan. Key Words: Henoch-Schoenlein purpura-Factor XIII—Elastase.
High Plasma Homocysteine: A Risk Factor for Arterial and Venous Thrombosis in Patients with Normal Coagulation Profiles
Authors: Kottke-Marchant Kandice , Green Ralph , Jacobsen Donald W. , Gupta Anjan , Savon Susan R. , Secic Michelle , Robinson Killian
Published: November 2007

A high plasma homocysteine concentration is associated with premature vascular disease and thrombosis. The association between high homocysteine concentrations and thrombosis in patients with a normal coagulation profile is unknown. Sixty adults (37 men and 23 women, mean age 46 years) with documented thrombosis were compared with age-and sex-matched controls. Those with risk factors for thrombosis or abnormal coagulation profiles were excluded. Homocysteine concentrations were higher in cases than controls (21.8 ± 13.8 vs 11.0 ± 4.7 μmol/L, p < 0.001). A cut point for defining high homocysteine concentrations was determined at 13 μmol/L and conferred an increased odds ratio for thrombosis overall (7.8, 95% CI 3.0-20.2, p < 0.001) as well as in men (8.9, 95% CI 3.0-26.1; p < 0.001) and women (37.8, 95% CI 6.5-213.9; p < 0.01). A high plasma homocysteine is a risk factor for thrombosis in patients with a normal coagulation profile. This common abnormality should be sought in patients with otherwise unexplained thrombotic episodes. Key Words: Homocysteine—Thrombosis—Clotting.
The Relationship of Various Factors in the Pathogenesis of Atherosclerosis
Authors: Sönmez Hüseyin , Süer Selma , Ulutin Turgut , Kökoglu Emine , Uçişik Nergiz
Published: November 2007

In this study we investigated the levels of lipid parameters, fibronectin, tissue-type plasminogen activator and plasminogen activator inhibitor (t-PA-PAI-1) complex and si alidase in patients with coronary heart disease and a control group. Total cholesterol, triglyceride, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol and lipoprotein Lp(a), levels in patients with coronary heart disease were found to be significantly higher than in the control group (p < .001). High-density lipoprotein (HDL) cholesterol levels in patient group were significantly lower than control group (p < .001). Plasma fibronectin and t-PA-PAI-1 complex levels in patients with coronary heart disease were found to be significantly higher than control group (p < .05 and p < .001, respectively). In addition, we found that serum sialidase levels in patients with coronary heart disease were significantly higher than in the control group (p < .001). The electrophoretic mobility of lipoproteins from patients with coronary heart dis ease was found to be greater than those from the control group. As a result Lp(a) may play an important role in the pathogen esis of atherosclerosis by causing foam cell formation because of interacting with LDL or fibronectin and by interfering with the fibrinolytic system because of binding to plasminogen re ceptors. In addition, modifications of Lp(a) (including desi alylation) may effect these events. Key words: Coronary heart disease—tPA-PAI-1 complex-Fibronectin-sialidase-Lipid parameters.
Pseudospontaneous Platelet Aggregation and Spuriously Elevated Blood Cell Counts in Cryoglobulinemia
Authors: Büyükaşik Yahya , Şemnur ileri N. , Haznedaroglu Ibrahim C. , Karaahmetoglu Selma , Müftüoğlu Osman , Kirazli Şerafettin , Dündar Semra
Published: November 2007

Cryoglobulinemia has been reported sometimes to cause false elevation in platelet and/or leukocyte counts in au tomated blood cell counters due to temperature-dependent pro tein precipitates that are falsely interpreted as blood cells at room temperature. Upon heating to 37°C, these blood counts decrease to normal levels as cryoproteins dissolve. Therefore, cryoglobulins could theoretically lead to erroneous diagnosis of spontaneous platelet aggregation in platelet counting and tur bidometric methods as platelet count and turbidity of the plate let-rich plasma decrease at 37°C, respectively. Here, the event of pseudospontaneous platelet aggregation is confirmed in two patients with mixed cryoglobulinemia, both had spuriously el evated blood cell counts.
Acquired Von Willebrand Factor Abnormalities in Adults with Congenital Heart Disease: Dependence Upon Cardiopulmonary Pathophysiological Subtype
Authors: Territo Mary C. , Perloff Joseph K. , Rosove Michael H. , Moake Joel L. , Runge Alice
Published: November 2007

Hemostasis is often abnormal in adults with con genital heart disease, and von Willebrand factor abnormalities have been reported in this patient population. We sought to determine the prevalence, type, and severity of the von Wil lebrand factor abnormality, and its relationship to three patho physiological variables; cyanosis, pulmonary vascular disease, and turbulent blood flow. This prospective study comprised 76 unoperated congenital heart disease patients aged 20 to 68 years (mean = 34 years). There were 44 cyanotic and 32 acyanotic patients. Twenty-seven cyanotic and 6 acyanotic pa tients had pulmonary vascular disease, 31 cyanotic and 16 acyanotic patients had turbulent blood flow, and 11 patients were acyanotic without pulmonary vascular disease or turbu lent flow. The largest plasma von Willebrand factor multimers were relatively decreased or absent in 77% of cyanotic versus 41 % of acyanotic patients ( p < .001); in 76% of patients with, versus 51 % without, pulmonary vascular disease ( p < .029); and in 72% of patients with, versus 45% without, turbulent flow ( p <.016). Von Willebrand factor multimers were normal in all 11 acyanotic patients without pulmonary vascular disease or turbulent blood flow. Von Willebrand factor multimer ab normalities normalized after reparative surgery in five patients. Depletion of the largest plasma von Willebrand factor multim ers is common in adults with congenital heart disease. Cyano sis, pulmonary vascular disease, and turbulent flow are deter minants of the abnormality that is acquired and reversible.
The Activated Protein C Resistance Phenotype of the Antiphospholipid Syndrome May Follow a Relapsing Course
Authors: Ruiz-Argüelles Guillermo J.
Published: November 2007

Activated protein C resistance, the most frequent thrombophilic condition may be inherited or acquired; the an tiphospholipid syndrome, either primary or secondary is one of the causes of the acquired form. The case of a patient with a primary form of antiphospholipid syndrome in whom the acti vated protein C resistance phenotype was assessed in four in stances during a 3-year period is presented. In two instances the abnormal phenotype of the activated protein C resistance was present, whereas in the other two it was absent. The factor V gene (G→A, 1691) leading to the (R 506 Q) factor V mutation, typical of most inherited forms of the activated protein C re sistance, was not found. The relapsing behavior of this phe nomenon has not been previously shown. The changing pattern of this abnormality could explain discordant previous reports about the prevalence of the activated protein C resistance phe notype in patients with primary or secondary forms of the an tiphospholipid syndrome.
Circadian Interrelationships Among Levels of Plasma Fibrinogen, Blood Platelets, and Serum Interleukin-6
Authors: Kanabrocki Eugene L. , Sothern Robert B. , Messmore Harry L. , Roitman-Johnson Beatrice , McCormick James B. , Dawson Susan , Bremner Fraser W. , Third Jane L. H. C. , Nemchausky Bernard A. , Shirazi Parvez , Scheving Lawrence E.
Published: November 2007

Circadian (24 h) rhythms of fibrinogen, interleu kin-6 (IL-6), and platelet levels were studied in 11 males ages 46 to 72 years. Since there is a known circadian rhythm for fibrinogen and IL-6, we postulated that the peak level (acro phase) of fibrinogen would follow the acrophase of IL-6, based on the fact that IL-6 is the stimulus for fibrinogen production in the liver. Platelet levels were measured to show whether there was any correlation with the IL-6 acrophase because it has been reported that IL-6 affects megakaryocytes and platelets in dogs. We found that the acrophase for IL-6 occurred at 02:03 h and the acrophase for fibrinogen occurred at 09:16 h. Platelet counts peaked at 16:56 h. Thus, there was a positive correlation between IL-6 and fibrinogen acrophases and a negative corre lation of each with the acrophase for platelets. The positive linkage of IL-6 with fibrinogen in this study suggests that sup pression of IL-6 production would lower those peak fibrinogen levels that occur in the morning in association with arterial ischemic events. This could result in fewer arterial ischemic events, especially in the morning. Key Words: Circadian— Fibrinogen—Interleukin—6 (IL-6)—Platelets—Arterial ischemia.
Heparin-induced Thrombocytopenia: Clinical Considerations of Alternative Anticoagulation with Various Glycosaminoglycans and Thrombin Inhibitors
Authors: Haas Sylvia , Walenga Jeanine M. , Jeske Walter P. , Fareed Jawed
Published: November 2007

Heparin-induced thrombocytopenia (HIT), the most common complication of heparin therapy, is also the most common form of the drug-induced thrombocytopenias. HIT is classified as type I and type II, the first being benign and the latter severe. HIT type II is attributed to an immune response characterized by complexes of heparin and platelet factor (PF) 4. Enzyme-linked immunosorbent assays allow easy and simple determination of these antibody titers; however, because speci ficity and sensitivity is not optimal, there is concern that the clinical relevance may be low. In clinical trials many patients were shown to form HIT-IgG in response to heparin without developing manifestations of HIT type II. Therefore, routine screening of clinically asymptomatic patients for antiheparin/ PF 4 antibodies is not recommended. HIT type II is a clinico pathologic syndrome that ideally should be confirmed by labo ratory testing. If any clinical suspicion arises, however, heparin and low molecular weight heparin therapy should be discon tinued and an alternative anticoagulant therapy started. Alter native drugs have been evaluated in significant numbers of patients including danaparoid and thrombin inhibitors. In the case of danaparoid, it is highly recommended that an in vitro test for cross-reactivity be performed before the onset of therapy. If testing cannot be performed, immediate administra tion of a thrombin inhibitor is preferred. Key Words: Plate lets—Heparin—Thrombocytopenia—Anticoagulants.
The G20210A Polymorphism in the 3' -Untranslated Region of the Prothrombin Gene in Mexican Mestizo Patients with Primary Antiphospholipid Syndrome
Authors: Ruiz-Argüelles Guillermo J. , Garcés-Eisele Javier , Ruiz-Delgado Guillermo J. , Alarcón-Segovia Donato
Published: November 2007

In an effort to identify alleles associated with an increased risk of venous thrombosis in patients with primary antiphospholipid syndrome, we studied the G20210A polymor phism (the G → A mutation at nucleotide position 20210) in the 3'-untranslated region of the prothrombin gene in a group of 14 patients with primary antiphospholipid syndrome. We did not find any patient with the mutated gene. Since the prothrom bin mutation is more prevalent in white populations, this find ing may be related with the genetic composition of the Mexican mestizos, in whom the white component is low. The polymor phism of the prothrombin gene in Mexican mestizo patients with antiphospholipid syndrome does not seem to be related to the thrombophilia observed in these patients.
Value of Thrombin-Antithrombin III Complexes in Major Orthopedic Surgery: Relation to the Onset of Venous Thromboembolism
Authors: Pazzagli Marcello , Mazzantini David , Cella Giuseppe , Rampin Ernesto , Palla Antonio
Published: November 2007

This study evaluated (a) the possible changes of plasma levels of thrombin-antithrombin III complexes during hospitalization to predict venous thromboembolism in patients undergoing elective total hip replacement and (b) the sensitivity and specificity of thrombin-antithrombin III complexes in the late incidence of deep vein thrombosis when these patients are discharged from the hospital. In 50 consecutive patients (18 men, mean age = 63 ± 8 years) a venous blood sample was obtained from each patient before surgery and postsurgery on days 5 ± 2, 9 ± 2, and 45 to evaluate the thrombin-antithrombin III complexes by the enzyme-linked immunosorbent assay as a part of a larger surveillance program. Six of 50 patients devel oped deep vein thrombosis, diagnosed by phlebography on the 45th day postsurgery. From the day before until the ninth day after surgery, mean values of the thrombin-antithrombin III complexes increased to a greater extent in patients with deep vein thrombosis than in those without, although the differences were not significant (from 14.8 ± 11.2 ng/mL to 36.2 ± 19.1 ng/mL in the former group and from 13.6 ± 3.3 ng/mL to 22.4 ± 5.1 ng/mL in the latter, p = NS). On the 45th day after surgery the mean value of the thrombin-antithrombin III com plexes reduced less in patients with deep vein thrombosis (up to 9.9 ± 1.9 ng/mL and to 25.2 ± 17.2 ng/mL, respectively, p = NS). In addition, thrombin-antithrombin III complexes re mained over the level reached on the fifth day only in the patients who developed deep vein thrombosis. On the 45th day after surgery, thrombin-antithrombin III complexes exhibited a sensitivity of 17%, a specificity of 86%, and an accuracy of 78% in differentiating the presence and absence of deep vein thrombosis as compared with phlebography. We conclude that after total hip replacement (a) serial measurement of the throm bin-antithrombin III complexes does not appear helpful in pre dicting venous thromboembolism during hospitalization, and (b) measurement of thrombin-antithrombin III complexes has a low diagnostic accuracy in diagnosing delayed deep vein thrombosis. However, the greater and persistent increase of thrombin-antithrombin III complexes level in patients who de veloped deep vein thrombosis may deserve further investiga tions.
Direct Measurement of Unfractionated Heparin Using a Biochemical Assay
Authors: Mielke C. Harold , Starr Christopher M. , Klock John C. , Devereaux Dawn , Mielke Marcia R. , Baker Danial E. , Broemeling Lyle , Wacksman Matt , White John R. , Oliver Sylvia A. , Ens Gordon , Gavin Patrick , Dittman William A.
Published: November 2007

A number of investigations have noted that func tional biological assays for heparin are not always reliable and may not reflect the actual biochemical level of heparin in pa tients receiving anticoagulant therapy. This creates the possi bility that patients receiving anticoagulant treatment may have an excess or deficiency of circulating levels of heparin. To address this problem, we have developed a direct biochemical measurement of heparin. The heparin assay uses fluorophore assisted carbohydrate electrophoresis (FACE) to directly mea sure the predominate disaccharide of unfractionated heparin. In this study, unfractionated heparin was measured in vitro throughout a wide range of heparin concentrations in plasma. Seven in vivo pharmacokinetic studies in five normal subjects given 3,000 USP units of unfractionated heparin intravenously showed a three-phase elimination process with higher peak plasma levels and shorter elimination times than predicted from previous studies. At these doses, heparin is largely eliminated intact through urinary excretion. Body weight has a significant effect on heparin kinetics. When we compared the direct bio chemical assay with two biological clotting assays, we found the latter can overestimate biochemical heparin concentrations. The FACE assay, due to its sensitivity, is also able to measure circulating levels of endogenous heparin in plasma and urine. Direct heparin measurement using the FACE technique is prac tical and useful for studies of the correlation of biochemical and biological activities.
An evaluation of six infusion devices for the continuous infusion of cytotoxic drugs in ambulatory patients
Authors: Hardy E.M. , Williamson C. , Sewell G.J.
Published: November 2007

Introduction. The clinical, economic, and user attributes of six ambulatory infusion devices were evaluated for their inclusion into the Home Oncol ogy Program, Exeter (HOPE).

Methods. Devices evaluated included; Graseby MS-26 syringe driver, Graseby 9100, Pharmacia CADD-1, Parker-Strato 2100 micropump (now un available), Baxter Multiday Infusor, and Infu-med 300. Criteria evaluated included accuracy, preci sion, in-use observations, capital cost, consumable cost, estimated monthly cost, degree of patient intervention, and patient comfort. A quality of life evaluation was undertaken in a more detailed assessment on the Graseby MS-26 and Infu-Med 300 device used routinely in the HOPE pro gramme.

Results. On the basis of these studies, the Parker-Strato 2100 pump was the preferred device although this has subsequently been withdrawn from the market. However, the newly developed Graseby 9000 series device was found to possess many of the qualities of the Parker-Strato pump and has been selected for further trials in this institu tion.
An extemporaneous itraconazole suspension for pediatric use
Authors: Seay Russell E. , Sommers Nancy L.
Published: November 2007

Objective. To report the use of an extemporane ously prepared acidic suspension of itraconazole for pediatric oncology patients.

Case Summary. Itraconazole was adminis tered to a 4-year-old AML patient with Alternaria sp sinusitis. An acidic itraconazole suspension was prepared using 0.1 N hydrochloric acid and cherry syrup. Bioassay for serum itraconazole suggested the product achieved adequate peak serum con centrations.

Discussion. Fasting and reduced gastric acid ity will decrease the absorption of itraconazole. The use of an acidic suspension provides more accurate dosing for pediatric patients, allows pro vision of itraconazole in an acidic media, and allows dosing in patients unable or unwilling to swallow capsules.

Conclusions. Itraconazole prepared in an acidic suspension appears to be absorbed. Further study is needed to establish stability of this prepa ration, as well as, the extent and consistency of its absorption.
Review : Amifostine and other chemoprotective agents in cancer chemotherapy: A brief review
Authors: Summerhayes Maxwell
Published: November 2007

Objective. Cytotoxic chemotherapy is a frequently, and increasingly, used treatment for malignant disease and is associated with substantial toxicity. A number of drugs have been developed in recent years for the prevention and treatment of chemotherapy-induced toxicity. Most are specific to one group of drugs, eg, mesna and the oxazophosphorines, or one type of toxicity, eg, the 5-HT3 antagonist antiemetics. The first multiorgan cytoprotective, amifostine, recently was launched, and another, glutathione, is under development. The purpose of this review is to con sider the agents currently available for the manage ment of cytotoxic drug-induced toxicity and their place in treatment. Special attention is directed to amifostine and drugs in development, including glu tathione, Ossirene (Baker Norton), ORG-2766, and dexrazoxane and less to agents in routine clinical use.

Data sources. A variety of sources were used, including manual and on-line (Medline) literature searching. Approved and other drug names were used as the primary search terms, linked with cytotoxic chemotherapy where limitation was required. Medi cal information departments of drug companies also were used where appropriate.

Study selection. Particular attention was directed to randomized clinical trials, but nonrandomised and animal studies were considered where appropriate.

Conclusions. Over the past decade significant advances have been made in the control of chemo therapy-induced toxicity and new agents promise even greater control. This is important, not only because they may improve the quality of life of conventionally treated cancer patients, but also be cause they should allow the dose-response relation ship for cytotoxic drug treatment to be fully explored. Unfortunately, the data available at present are insuf ficient to determine the extent to which this promise will be fulfilled.