bluuebunny/crossref_metadata_2025 huggingface dataset:
The Treatment of Proximal Vein Thrombosis with Subcutaneous Low-Mole Molecular-Weight Heparin Compared with Continuous Intravenous Heparin
Authors: Hull Russell D. , Raskob Gary E. , Pineo Graham F. , Brant Rollin F.
Published: November 2007

Low-molecular-weight heparin, compared with unfractionated heparin, has a higher bioavailability and a more prolonged half-life. There are limited data comparing the use of low-molecular-weight heparin with unfractionated heparin for the treatment of deep vein thrombosis. We have compared fixed-dose, subcutaneous low-molecular-weight heparin given once daily with adjusted-dose intravenous heparin given by continuous infusion in a multicenter double-blind clinical trial for the initial treatment of patients with proximal vein thrombosis. Clinical outcomes were objectively documented. Six of 213 patients receiving low-molecular-weight heparin (2.8%) and 15 of 219 patients receiving intravenous heparin (6.9%) developed new episodes of venous thromboembolism (p = 0.07; 95% confidence interval for the difference, 0.02%-8.1%). During initial therapy, major bleeding occurred in one patient receiving low-molecular-weight heparin (0.5%) and in 11 patients receiving intravenous heparin (5.0%), a risk reduction of 91% (p = 0.006). This apparent protection against major bleeding was lost during long-term therapy. Minor bleeding complications were rare. During the period of the study, 10 patients receiving low-molecular-weight heparin (4.7%) died, as compared with 21 patients receiving intravenous heparin (9.6%), a risk reduction of 51%(p = 0.049). This study shows that low-molecular-weight heparin is at least as effective as classic intravenous heparin therapy and that there was a reduction in deaths and bleeding complications. Furthermore, low-molecular-weight heparin was more convenient to administer. The simplified therapy with low-molecular-weight heparin given by once-daily subcutaneous injection without monitoring may allow patients with uncomplicated proximal deep vein thrombosis to be cared for as outpatients. Key Words: Low-molecular-weight heparin—Unfractionated heparin—Deep vein thrombosis—Deaths—Bleeding complications.
Minidose Warfarin and Failure to Prevent Deep Vein Thrombosis After Joint Replacement Surgery Despite Inhibiting the Postoperative Rise in Plasminogen Activator Inhibitor Activity
Authors: Poller Leon , Thomson Jean M. , MacCallum Peter K. , Nicholson David A. , Weighill Frank J. , Lemon Jerry G.
Published: November 2007

In a prospective randomised study in patients undergoing elective total hip or knee replacement surgery, the antithrombotic efficacy of fixed-minidose warfarin (1 mg daily commenced 7 days before surgery) was compared with that of subcutaneous calcium heparin (Calciparine, 5,000 IU t.d.s. commenced 2 h before surgery). Both regimens were continued until venography of the operated limb was performed 9-14 days postsurgery. Venographically detected deep vein thromboses (DVTs) occurred in 15 of the 31 patients (48.4%) in the minidose warfarin group and in eight of the 37 patients (21.6%) receiving heparin. The absolute difference in the incidence of DVT was 26.8% in favour of heparin (95%l confidence interval [CI] -4.&--48.8%; p = 0.039). Proximal DVTs were detected in three patients receiving minidose warfarin and in none of those on heparin (p = 0.09). Minidose warfarin appeared to prevent the postoperative rise in the activity of plasminogen activator inhibitor (PAI) that occurred with heparin, although preoperative PAI activity was greater in the warfarin group. The prothrombin time (PT) and activated partial thromboplastin time (APTT) were within the normal range on the day of surgery in both treatment groups. Postsurgery, the minidose warfarin regimen produced a small, but significant prolongation of the PT compared with the group receiving heparin, In contrast to heparin, 1 mg warfarin daily failed to prevent postoperative acceleration of the APTT. There was no significant difference between the two regimens in bleeding complications. In conclusion, the fixed-minidose warfarin regimen cannot be recommended for prevention of DVT after hip or knee replacement surgery. Inhibition of the postoperative rise in PAI activity appears not to protect against DVT after major joint replacement surgery. Key Words: Warfarin—Heparin—Deep vein thrombosis prophylaxis—Coagulation—Fibrinolysis— Plasminogen activator inhibitor.
State-of-the-Art Review : Role of Antithrombin and Tissue Factor Pathway Inhibitor in the Control of Thrombosis and Mediation of Heparin Action
Authors: Iverson Nina , Abildgaard Ulrich
Published: November 2007

Deficiency of any of the two coagulation in hibitors antithrombin (AT) and tissue factor pathway in hibitor (TFPI) lowers the resistance to thrombosis. He reditary deficiency of AT leads to a high risk of throm bosis, which occasionally responds poorly to heparin therapy. Experimental deficiency of TFPI lowers the re sistance to infusion of both tissue factor and endotoxin, both regarding microvascular thrombosis and fatality. Administration of either AT or TFPI protects against mi cro- and macrovascular thrombosis. Injection of heparin and some other glycosaminoglycans releases intima bound TFPI to the blood. Heparin accelerates the inhib itory effects of both inhibitors, in particular the effect of AT. The influence of the two inhibitors on the various anticoagulant reactions have been studied using blocking antibodies. It is suggested that the anticoagulant and an tithrombotic effects of heparin are mainly mediated by the accelerated inactivation of thrombin, factor IXa and factor X by AT, and augmented inactivation of tissue factor-factor VIIa by TFPI released to the blood.
Erythropoietin and Desmopressin Obviated Transfusion in a Thromboasthenic Jehovah's Witness Undergoing Scoliosis Surgery
Authors: Lethagen Stefan , Karlsson Magnus K.
Published: November 2007

A 13-year-old female Jehovah's Witness with thromboasthenia was scheduled for scoliosis surgery. To reduce the risk of heterologous transfusion, she was given erythropoietin for 2 weeks preoperatively. Bleeding time and platelet dysfunction normalized during erythropoietin treatment, but the hemoglobin concentration increased only marginally. Desmopressin and tranexamic acid were given as cover for surgery. Blood loss was less than that in the average scoliosis patient, 1,490 ml as compared to 2,740 ml, and no heterologous transfusion was given. Erythropoietin may thus be given preoperatively, not only to increase the hemoglobin concentration, but also to improve the platelet function in thromboasthenic pa tients.
Low Risk of Subsequent Deep-Venous Thrombosis in Patients with a Negative Venous Duplex Scan
Authors: Bona Robert , Hickey Amy , Greenwald Lori , Sullivan Eugene , Livadiotis Panos , Johnson Ora , Kulak Andrea , Wajcs Selby , Vose Kathy
Published: November 2007

Venous duplex scanning (VDS) is sensitive and specific for proximal deep-vein thrombosis (DVT) but has poor sensitivity for isolated calf DVT, some of which can extend to the proximal veins and result in clin ically significant pulmonary emboli. The intent of this study was to determine the long-term outcome of outpa tients with negative VDS and to assess the accuracy of three biochemical markers of hypercoagulability for the detection of DVT. Consecutive ambulatory patients re ferred to our vascular laboratory with a question of lower extremity DVT had plasma determination of D-dimer, prothrombin fragment 1.2, and thrombin-antithrombin complex. Additionally, patients with a negative VDS were followed for 6 months to determine the frequency of subsequent venous thrombosis. Of 207 patients seen in our vascular laboratory, 171 had either a single negative VDS or two negative studies (done 24-72 h apart). Fol low-up of 161 patients for 6 months showed no evidence of venous thromboembolism. The remaining 10 patients died from other causes or had alternative diagnoses made to explain their symptoms. The D-dimer and thrombin- antithrombin complex had equal test accuracy for the di agnosis of DVT and were superior to the prothrombin fragment 1.2 levels. Symptomatic venous thromboembo lism occurring after negative VDS is uncommon. D-dimer and thrombin-antithrombin levels have equal utility as diagnostic tests for DVT.
Perinatal Intracranial Hemorrhage as First Manifestation of Congenital Hypofibrinogenemia
Authors: Paolini Rossella , Sartori Maria Teresa , Fiorin Francesco , Gorinati Marino , Boeri Giuseppe , Girolami Antonio
Published: November 2007

We describe a new case of congenital hypofi brinogenemia revealed by the dramatic occurrence of a perinatal intracranial hemorrhage, which resulted in dif fuse multicystic encephalopathy with severe hydroceph alus. The family history was negative for hemorrhagic tendency, but the assessment of a complete coagulation study showed the presence of low fibrinogen coagulant and antigen plasma levels both in the patient and in her 5-year-old healthy sister. Because the hereditary trans mission of the disease is autosomal recessive, similar fi brinogen concentrations were expected in the two af fected sisters. However, the patient showed lower levels than the sister (14 mg/dl and 46 mg/dl, respectively): a different phenotypic expression of the disorder or the dif ferent age of the two sisters could provide some explana tion. Moreover, we emphasize the importance of neonatal coagulative screening for the diagnosis of such defects.
State-of-the-Art Review : Treatment of Hemodialysis Access Failure: A Role for Thrombolysis
Authors: Sands Jeffrey J. , Miranda Carol L.
Published: November 2007

Thrombosis of hemodialysis accesses remains a major source of morbidity, hospitalization, and expense for patients with end-stage renal disease. Treatment of hemodialysis accesses includes strategies to prevent ac cess failure and methods for treating acute thromboses. Such techniques as Doppler ultrasonography, venous pressure monitoring during dialysis, measurement of ra tios of venous to systemic pressures, and measurement of recirculation have been used to predict accesses at risk of thrombosis. Elective interventions, including surgical re visions and angioplasties, have been shown to lessen the thrombosis rate in both polytetrafluoroethylene (PTFE) grafts and arterio-venous fistulas. Elective revision has also improved long-term patency of both grafts and fistu las when compared with repairing the accesses only after thrombosis. Despite these attempts, acute thrombosis of hemodialysis accesses remains a common complication for patients with end-stage renal disease. Historically, surgical thrombectomy has been the gold standard for treatment of acute hemodialysis access failure. Over the past 10 years, thrombolytic therapy has gained an in creasing role in the treatment of acutely thrombosed PTFE grafts. Thrombolysis has had at least comparable results to surgical thrombectomy in the best centers, with similar complication rates. Thrombolytic therapy is also significantly less expensive than surgical thrombectomy. In summary, we believe that hemodialysis access treat ment should encompass a comprehensive program, in cluding access surveillance to select accesses at risk of failure. Elective intervention should be performed in an attempt to prevent thrombosis and increase long-term ac cess patency. When thrombosis does occur, pharmaco mechanical thrombolysis is the preferable first interven tion for acutely occluded PTFE hemodialysis accesses.
Coagulation and Fibrinolysis in Amyloid and Non-amyloid Hemodialysis Patients: Assessment of Local Hemostatic Kinetics Within Arteriovenous Fistulas
Authors: Erdem Yunus , Haznedaroglu Ibrahim C. , Çelik Ismail , Yalçin Ahmet U. , Yasavul Ünal , Turgan Çetin , Kirazli Serafettin , Çağlar Şali
Published: November 2007

This study was designed to determine whether systemic amyloidosis is an additional risk factor for he mostatic abnormalities in hemodialysis patients and to evaluate local alterations of the hemostatic process within the patent-functional native arteriovenous fistula (AVF). Concentrations of in vivo molecular hemostatic markers, including prothrombin fragment1 +2 (PF 1.2), thrombin antithrombin III complex (TAT) and plasmin-α 2 antiplasmin complex (PAP) were determined in plasma samples taken simultaneously from AVFs and contralat eral upper extremity large veins of hemodialysis patients associated with and without systemic amyloidosis. Seven amyloid (2 women, 5 men, aged 34 ± 6 years), and 13 non-amyloid patients (4 women, 9 men, aged 36 ± 7 years) on maintenance hemodialysis and 20 healthy vol unteers (8 women, 12 men, aged 36 ± 9 years) were in cluded in the study. Peripheral vein PF 1.2 and TAT lev els showed no difference between amyloid and non- amyloid patient groups, but both were significantly higher than control group. PF 1.2 and TAT levels were also found to be elevated in fistulas when compared with that of peripheral vein in both amyloid and non-amyloid pa tient groups. Determination of PAP in peripheral veins of each group revealed significantly higher levels in amyloid hemodialysis patients than in non-amyloid patients and controls. PAP levels were significantly higher in fistulas of amyloid patients than in non-amyloid patients. In con clusion, this study confirms enhanced coagulation and fibrinolysis in hemodialysis patients and excessive fibri nolysis in amyloid patients with remarkable contribu tion of AVF on enhanced coagulation and fibrinolysis.
Systemic Lupus Erythematosus Presenting as Superior Vena Cava Syndrome Associated With Anticardiolipin Antibodies
Authors: Erdem Yunus , Haznedaroğlu Ibrahim C. , Oymak Oktay , Yalçin Ahmet Ugur , Yasavul Ünal , Turgan Çetin , Çağlar Şali
Published: November 2007

A case of systemic lupus erythematosus (SLE) presenting as superior vena cava syndrome is pre sented. This 19-year-old woman was admitted for head ache and swelling in her face and neck. Initial evaluation revealed that she had a superior vena cava syndrome. Thoracal computed tomography (CT) and intravenous digital substraction angiography demonstrated the occlu sion in the superior vena cava. ANA and antiDNA titers were high and anticardiolipin antibodies were positive. Along with immunosuppressive treatment, she had been administered intravenous streptokinase. To our knowl edge, no SLE patient presenting with such an unusual form has been described in the English literature.
Use of Recombinant Factor VIIa for Major Elective Surgery in a Patient with Factor VII Deficiency, Retroperitoneal Fibrosis and Hydronephrosis
Authors: Cobos Everardo , Keung Yi-Kong , Akhter Saeed , Jones Jeff
Published: November 2007

We described a case of obstructive uropathy due to retroperitoneal fibrosis associated with congenital factor VII deficiency. Nephrectomy and ileoureter reconstruction was performed uneventfully using recombinant factor Vlla perioperatively. There was no excessive bleeding or thrombosis. Key Words: Recombinant factor Vlla-rFVlla-Retroperitoneal fibrosis-Factor VII deficiency.
State-of-the-Art Review: Molecular Markers in Thrombosis and Hemostasis
Authors: Amiral J.
Published: November 2007

Molecular markers for exploring the different stages of hemostasis activation are now available. These markers allow investigation of endothelial functions, blood cell activation, stimulation of coagulation pathways, involvement of the fibrinolytic system, and profiling of the coagulolytic-equilibrium that regulates hemostasis. Additionally, these markers find useful applications for monitoring therapies, following-up clinical states associated with high thrombotic risk, and validating new drugs and analyzing their mode of action. Furthermore, these markers may allow for recognition of the evolution of early disease in the clinically silent phase. Large scale epidemiological and longitudinal studies are required for establishing this latter approach. Up to now, only D. Dimer is used in routine clinical application for exclusion diagnosis of deep-veinous-thrombosis and pulmonary embolism. Other markers must prove their sensitivity for the early asymptomatic period and demonstrate their applicability throughout disease evolution. According to pathology and application, different markers may provide complementary information. Some markers, e.g., D. Dimer, soluble thrombomodulin, and modified AT-III (ATM), are used on standard citrated plasma samples. Modem and flexible technologies are now available for point-of-care testing (when required), quick and sensitive measurements in emergency conditions, and full automation when necessary. Lastly, factors that trigger hemostatic activation can now be evaluated and provide information on etiology. In this latter respect, autoimmunity may be important in thrombotic disease induction. Key Words: Hemostatic activation—Molecular markers— Thrombosis—Predictivity—Monitoring antithrombotic therapies.
State-of-the-Art-Review: Microvesicles in Blood Components: Laboratory and Clinical Aspects
Authors: Krailadsiri Pranee , Seghatchian Jerard , Bode Arthur P.
Published: November 2007

There is ample evidence for the presence of microvesicles (MV) of different sizes and functions in various blood components. A variety of mechanisms have been proposed for the formation of MV. These include mechanical injury, shear stress, cell activation, activation of complements, hypoxia, and the cell aging process. While MV share many biological properties and surface receptors of their parental cells, they demonstrate significant differences in membrane asymmetry of the inner membrane phospholipid, in particular phosphatidylserine (PS). This provides high-affinity binding sites for the components of the prothrombinase complex. To what extent these MV contribute to hemostatic effectiveness, immudomodulation, and some untoward effects of the transfused blood components remains to be fully elucidated. Several methods for qualitative and semiquantitative characterization of MV are now available. Although in most cases it is necessary to separate MV from the intact cells for improved characterization, recent advances in flow cytometry make it possible to accurately differentiate MV in the presence of their parental cells on the basis of light scattering and fluorescent intensity. This review focuses on four main areas of MV in blood components: (1) the proposed mechanisms of platelet vesiculation, (2) factors influencing the formation of MV, (3) laboratory analysis of MV, and (4) the clinical impact of the presence of MV in blood components. Key Words: Microvesicte—Vesicutation—Biood component—Ptatelets—Transfusion.
Concept and Clinical Application of Platelet Glycoprotein IIb/IIIa Inhibition with Abciximab (c7E3 Fab; ReoPro) for the Prevention of Acute Ischemic Syndromes
Authors: Anderson H. Vernon , Jordan Robert E. , Weisman Harlan F.
Published: November 2007

The platelet membrane glycoprotein (GP) IIb/IIIa integrin receptor is the final common pathway leading to platelet aggregation. Local aggregation commonly occurs following atherosclerotic plaque rupture or other injury to the vascular wall. When GP IIb/IIIa is activated, fibrinogen and von Willebrand factor bind to the receptor with high affinity, crosslinking platelets and locking them to the vessel surface and to each other. This process is central to arterial thrombus formation and consequent acute coronary syndromes, such as myocardial infarction (MI), unstable angina, and abrupt closure following revascularization procedures. Abciximab (c7E3 Fab; ReoPro) is a chimeric monoclonal antibody fragment developed specifically to inhibit GP IIb/IIIa receptor activity and thus prevent platelet aggregation and thrombosis. Abciximab has been evaluated in several clinical studies, the largest of which was the Evaluation of Abciximab for the Prevention of Ischemic Complications (EPIC) trial. This randomized, multicenter, placebo-controlled trial enrolled 2,099 patients at high risk for ischemic complications following coronary revascularization. The patients were randomized into three treatment groups: placebo, abciximab bolus (0.25 mg/kg), or abciximab bolus plus 12-h infusion (10 μg/min). Patients in the abciximab bolus plus infusion group had significant reductions, compared with placebo, in a composite end point of death, nonfatal MI, and urgent coronary intervention within 30 days. These positive, short-term findings were maintained at 6 months of follow-up. Bleeding complications and transfusions were significantly increased in abciximab patients, although there was no increase in bleeding-related death, stroke, or surgery. Retrospective secondary analyses suggested that many of the bleeding events observed in the EPIC trial may have been associated with concomitant high-dose heparin therapy, particularly in lighter weight patients. Subsequent clinical trials have shown that bleeding events can be reduced in patients treated with abciximab by using weight-adjusted heparin dosing without affecting the efficacy of the abciximab bolus plus infusion regimen. Examination of health economic data from the EPIC trial showed that abciximab bolus plus infusion is cost effective as well as clinically beneficial. These results confirm the importance of platelet GP IIb/IIIa receptor blockade in the treatment of acute thrombotic syndromes. Key Words: Platelet aggregation—GP IIb/IIIa receptor—Coronary revascularization— Ischemia.
Isolated Iliac Vein Thrombosis During Oral Contraceptive Therapy in Three "Normal" Women
Authors: Girolami Antonio , Prandoni Paolo , Zanardi Alessandra , Girolami Bruno , Zanon Ezio
Published: November 2007

Isolated iliac vein thrombosis appears to be a rare clinical entity. It is usually due to extrinsic compression on the iliac vein with consequent stasis. Diagnosis may be difficult since compression ultrasonography is usually negative. Only phlebography is surely diagnostic. This procedure should be carried out whenever there is a discrepancy between the clinical evaluation and a negative sonography. We report three women on oral contraceptive therapy in whom a diagnosis of isolated iliac vein thrombosis was suspected clinically and confirmed phlebographically. No other congenital or acquired potential cause of thrombosis was present in the propositae but for the oral contraceptives. Oral contraceptives had been taken for 12, 3, and 2 months respectively for three patients before thrombosis occurred. Two of the propositae were 25 years old and the third was 54. The latter patient had been given oral contraceptives to "prevent osteoporosis" after menopause. The discontinuation of the pill together with usual heparin and coumarin therapy were effective in every instance. A specific pathogenic role of the oral contraceptives may be surmised. In fact, no isolated iliac vein thrombosis was found in a control group of 20 women of fertile age we showed to have idiopathic deep vein thrombosis of the legs. This article emphasizes once again the importance of a careful clinical evaluation in the suspicion of deep vein thrombosis. Key Words: Oral contraceptive therapy-Deep vein thrombosis-Iliac vein thrombosis.
Reperfusion After Venous Occlusion Caused Transient Increase in Plasminogen Activator Inhibitor-1 in Systemic Circulation
Authors: Nagai Nobuo , Urano Tetsumei , Takada Yumiko , Takada Akikazu
Published: November 2007

From the point of local regulation, we investigated fibrinolytic activity both in local and systemic circulations, using a venous occlusion test as a stimulus of tissue plasmin ogen activator (t-PA) release in human volunteers. Blood samples were taken before, during, and after venous occlusion from the occluded arm as trapped blood and the unoccluded arm as blood of systemic circulation. In these samples, fibri nolytic activity by euglobulin-clot lysis time and related factors in t-PA and plasminogen activator inhibitor-1 (PAI-1) were measured. Venous occlusion increased fibrinolytic activity ac companied by an increase in t-PA without an increase in PAI-1 on the occluded arm. The fibrinolytic activity on the unoc cluded arm did not change. Five minutes after reperfusion, however, a transient increase in PAI-1 and no change of fibri nolytic activity were observed in the unoccluded arm. Transient increase of PAI-1 after reperfusion was also observed in the occluded arm. These results suggested that increased t-PA by venous occlusion was neutralized by released PAI-1 after reperfusion. Key Words: Tissue-plasminogen activator— Euglobulin-clot lysis time—Fibrinolysis.
High Concentrations of Thrombopoietin Activate Platelets In Vitro
Authors: Hammond William P. , Wun Theodore , Kaplan Alexander , Kaplan Svetlana , Paglieroni Teresa , Kaushansky Kenneth , Foster Donald C.
Published: November 2007

Thrombopoietin (TPO), the ligand for the proto- oncogene c-mpl, has been cloned and expressed from both human and murine sources. Thrombopoietin increases platelet counts when given in vivo and acts on progenitor cells to in crease their proliferation and maturation into megakaryocytes. The effects of TPO on mature platelets were investigated by evaluating platelet aggregation and platelet activation- dependent antigen expression. Platelet aggregation score, a quantitative representation of aggregation, showed potentiation of response to ADP-induced aggregation but no direct agonist response to TPO alone. Soluble c-mpl blocked the effect of TPO on the platelet aggregation score. Flow cytometry showed that TPO at concentrations >250 U/ml (50 ng/ml) caused a minority population of platelets to express the activation mark ers CD62, CD63 and activated glycoprotein IIb/IIIa. While stem cell factor and interleukins-3 and -6 did not affect platelet activation antigen expression, interleukin-11 increased CD62 expression on platelets in vitro. The effects of TPO on antigenic expression and aggregability were partially inhibited in vitro by preincubation with aspirin. We conclude that high concentra tions of TPO promote platelet activation antigen expression on a proportion of platelets and potentiate platelet aggregability to ADP in vitro by a process that is partially inhibited by aspirin.
Heparin and Low Molecular Weight Heparin Prolong Prothrombin Times in Patients on Warfarin Treatment
Authors: Strekerud Finn G. , Abildgaard Ulrich
Published: November 2007

Most commercially available prothrombin (PT) as says are stated to be insensitive to heparin in therapeutic doses. These conclusions are, however, based on studies using normal plasma samples. The aim of the present study was to study the effect of unfractioned heparin, three low molecular heparins, and a heparinoid on six prothrombin assays using plasma samples from patients on warfarin. Plasma samples from 30 patients on warfarin were heparinized in vitro with unfrac tioned heparin, three different low molecular weight heparins (Fragmin® [Pharmacia/Upjohn Inc., Delaware, U.S.A.], Klex ane® [Rhone Poulenc Rorer, Halte, Denmark], and Logiparin- Dinnohep®, [Leo Biological Products, Ballerup, Denmark]) and the heparinoid Org 10172 (Orgaran [Organon, Oss, The Netherlands]) to obtain 0.50-1.50 U/ml plasma. The PT time was then determined with four PT reagents stated to be insen sitive to heparin (Innovin [Dade, Miami, Florida, U.S.A.], Ny coplastin [Nycomed Pharma, Oslo, Norway], Nycotest PT [Ny comed Pharma], and Stago Prothrombin Complex Assay [SPA 50, Diagnostica Stago, Franconville, France]) and two reagents stated to be sensitive to heparin (Manchester Reagent [Manchester Comparative Reagent, Ltd., Stockport, Great Brit ain] and Thrombotest [Nycomed]). All PT assays except Inno vin were sensitive to the heparins. With a heparin concentration of 0.5 U/ml plasma, the increase in INR ranged from 18-55% with Thrombotest and 0-44% with the other assays. The in crease in INR values by 1.5 U/ml plasma differed among the heparins used; Manchester Reagent 6-297%, Thrombotest 43- 247%, Nycoplastin 48-81%, SPA 50 20-74%, Nycotest PT 17-36%, and Innovin 0-5%. Orgaran did not prolong the clot ting time with the Manchester Reagent. With the other five PT assays, Innohep (Leo Biological Products, Ballerup, Denmark) and Orgaran gave the largest increase in INR value. Fragmin, Klexane, and unfractioned heparin caused a similar low in crease in INR. A 3-h delay in testing prolonged the prothrom bin times with the simple PT assays (Manchester Reagent and Nycoplastin). The other assays were little affected. Concomi tant heparin therapy prolongs the PT clotting times with all reagents, except Innovin, to the extent that with three of the assays examined this may lead to underdosing of warfarin.
The Influence of Labor and Placental Separation on Hemostasis in Term Pregnancy
Authors: Koh Stephen C. L. , Arulkumaran Sabaratnam , Biswas Arijit , Ratnam S. Shan
Published: November 2007

We studied the hemostatic effects in 68 term preg nant subjects with normal pregnancy (n = 39), gestational diabetes mellitus (n = 21), pregnancy-induced hypertension (n = 8), during labor, after placental separation, and at 24 hours postpartum. During labor, a hypercoagulable state with en hanced fibrinolysis and platelet activation along with elevated plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 were seen. In all cases following placental separa tion, enhanced fibrinolysis persisted with further elevated tissue plasminogen activator antigen and D-dimer levels, increased thrombin generation and platelet activation with decreasing plasminogen activator inhibitor-1 levels. By 24 hours postpar tum, thrombin generation (thrombin-antithrombin complex) decreased to a nonpregnant level except for pregnancy induced hypertension, but enhanced prothrombin activation (F1+2) was evident in normal, gestational diabetes mellitus and pregnancy- induced hypertension. Reduced total protein S and antithrom bin III activity with normal protein C and elevated fibrinogen levels seen during labor were not affected by delivery. How ever, although factor VII showed a decreasing trend at 24 hours postpartum it remained elevated above the normal nonpregnant level. At 24 hours postpartum, a hypercoagulable state still persisted in normal, gestational diabetes mellitus and preg nancy-induced hypertension term pregnancy accompanied by enhanced fibrinolysis and elevated plasminogen substrate for fibrinolysis, suggesting a critical dynamic equilibrium between a thrombotic and hemorrhagic state.
Comparison of Unfractionated Versus Low Molecular Weight Heparin for Deep Vein Thrombosis Prophylaxis During Breast and Pelvic Cancer Surgery: Efficacy, Safety, and Follow-up
Authors: Heilmann Lothar , Tempelhoff Georg-Friedrich V. , Kirkpatrick Charles , Schneider Dirk M. , Hommel Gerhard , Pollow Kunhard
Published: November 2007

In a prospective, double-blind randomized trial the efficacy and safety of low molecular weight heparin and un fractionated heparin were compared for the prevention of post operative deep vein thrombosis in patients undergoing major surgery for breast and pelvic cancer. Three hundred fifty-eight patients were randomly allocated to the two treatment groups. Thirty-four of these were excluded from the study. Of the re maining 324 patients, 164 received 5000 IU unfractionated heparin three times daily and 160 received 3000 anti-Xa units of low molecular weight heparin once daily. Treatment was started 2 to 5 hours preoperatively and continued for 7 days. The occurrence of deep vein thrombosis was determined by impedence plethysmography and/or venography. Deep vein thrombosis was diagnosed in 10 (6.3%) of 160 patients taking low molecular weight heparin and 10 (6.1 %) of 164 patients treated with unfractionated heparin (relative risk: 1.03; 95% confidence interval 0.44-2.39; p = 1.0). Major bleeding events occurred in 27 (16.8%) patients in the low molecular weight heparin group and 47 (28.7%) in the unfractionated heparin group (relative risk: 0.59; 95% confidence interval: 0.39-0.89; p = .01). Severe intraoperative bleeding was observed in three patients in the unfractionated heparin group and in none of the patients in the low molecular weight heparin group. Excessive intraoperative bleeding was less frequent in the low molecular weight heparin group (9.4% vs. 14%, p = .23) as was wound hematoma (11.3 vs. 17.7%, p = .12). Bleeding episodes with low molecular weight heparin were less likely to lead to further surgery for evacuation of hematoma (0.6% vs. 2.5%, p = .37). Perioperative death rate was 3.1 % in the low molecular weight heparin group and 1.8% in unfractionated heparin group (rela tive risk: 1.72, 95% confidence interval: 0.42-7.07; p = .49). Follow-up data were available for 316 patients for an average of 20 months after surgery. There were 35 further cancer deaths (11 low molecular weight heparin group, 24 unfractionated heparin group) and 23 patients with late onset thromboembolic complications (11 low molecular weight heparin group, 12 un fractionated heparin group). The two drugs were of similar efficacy but the frequency of major bleeding was 41.1% less in the low molecular weight heparin group.
Aberrations of the Tissue Factor Pathway in Patients Positive for Lupus Anticoagulant
Authors: Wakita Yoshihiko , Wada Hideo , Nakase Tutomu , Nakasaki Takahiro , Shimura Minori , Hiyoyama Katuzo , Mori Yoshitaka , Gabazza Esteban C. , Nishikawa Masakatu , Deguchi Katsumi , Shiku Hiroshi
Published: November 2007

To evaluate the relationship between the tissue factor (TF) pathway and lupus anticoagulant (LA), in the pres ent study, we measured the plasma levels of TF antigen and TF pathway inhibitor (TFPI) antigen in patients positive for LA. Plasma TF and TFPI levels in LA-positive patients were sig nificantly higher than levels in healthy volunteers (p < 0.01). In LA-positive patients, there were no significant differences in plasma TF and TFPI levels between patients with and without thrombosis. In patients with thrombosis, there was no signifi cant difference in the plasma TF level between LA-positive and LA-negative patients; however, the plasma TFPI level in LA- positive patients was significantly lower than that in LA- negative patients (p < 0.01). We also examined the TF pathway in human umbilical venous endothelial cells (HUVEC) incu bated with plasma of LA-positive patients, LA-negative pa tients, and healthy volunteers. TF activity was significantly higher (p < .05) in HUVECs incubated with the plasma of LA-positive patients than in cells incubated with the plasma of the other two groups (p < .01). However, there was no signifi cant difference in TFPI antigen levels among the media of HUVECs incubated with the plasma of all groups. The viability of HUVEC incubated with the plasma of LA-positive patients with thromboses, LA-positive patients without thromboses, and LA-negative patients with thromboses were significantly lower than that of HUVECs incubated with the plasma of healthy volunteers (p < .01). These findings suggest that abnormalities of the TF pathway plays an important role in the mechanism of hypercoagulability in LA-positive patients. LA may affect vas cular endothelial cells causing thrombogenesis. Key Words: Lupus anticoagulant—Tissue factor—Tissue factor pathway inhibitor—Vascular endothelial cell—MTT assay.
Cytoskeletal Organization and Incorporation of β3 Integrin in Thrombin-stimulated Platelets: Effect of Acetylsalicylic Acid
Authors: Yukie Maeda Nair , Lopes Antonio Augusto B. , Bydlowski Sergio P.
Published: November 2007

Platelet stimulation by agonists is followed by changes in cytoskeletal organization that includes actin poly merization and association of the membrane skeleton (which is connected with the integrin αIIbβ3) with the underlying cyto plasmic actin filaments. The effect of orally administered ace tylsalicylic acid to healthy volunteers on incorporation of con tractile protein and β3 integrin into the cytoskeletal core of thrombin-stimulated platelets was studied. Stimulation was fol lowed by increased contractile protein and β3 incorporation into the cytoskeleton. Acetylsalicylic acid intake resulted in decreased incorporation of myosin and actin (32% and 20%, respectively), and a decrease (36%) in the association of β3 integrin with the cytoskeletal elements was evident. In conclu sion, we have shown that acetylsalicylic acid, besides the known inhibitory effect on thromboxane synthesis, promotes changes in the cytoskeletal organization of thrombin-stimulated platelets that could limit thrombus formation. Key Words: β3 integrin (glycoprotein IIIa)—Acetylsalicylic acid—Platelet cytoskeleton.
Anticoagulant Therapy of Pregnant Patients with Prosthetic Heart Valves : Rationale for a Clinical Trial of Low Molecular Weight Heparin
Authors: Messmore Harry L. , Kundur Ramesh , Wehrmacher William , Scanlon Patrick
Published: November 2007

The management of anticoagulant therapy for the prevention of thromboembolism from prosthetic heart valves in the pregnant patient is far from ideal and deserves more clinical research. Warfarin therapy given alone throughout pregnancy poses high risks to the fetus because it crosses the placental barrier. Heparin alone throughout pregnancy poses high risks to the mother, which might be lessened somewhat by more inten sive therapeutic regimens and careful monitoring of the heparin level or anticoagulated state of the blood. Because of the major risk of embryopathy in the fetus during the first trimester and latter half of the third trimester, heparin therapy during those times has been recommended. In the opinion of some experts, high-risk cases may benefit from low-dose aspirin in addition to anticoagulant therapy. The fact that warfarin is contraindi cated during pregnancy (according to the pharmaceutical com pany that markets it) poses some problems for the physician who prescribes it. For the above reason, alternative drugs are worthy of consideration and should be given clinical trials. Low molecular weight heparin has the potential for greatly reducing drug-related risk for the fetus while providing greater safety for the mother.
State-of-the-Art Review : Acquired APC Resistance in Neurosurgical Patients May Not Be a Risk Factor for Postoperative Deep Vein Thrombosis
Authors: Meinardi Johan R. , Henkens Cilia M. A. , de Kam Pieter-Jan , Van der Meer Jan
Published: November 2007

Acquired resistance to activated protein C has been reported during oral contraception and pregnancy. Its thrombogenic potential was studied in 41 neurosurgical pa tients who were enrolled in the placebo group of a thrombo prophylaxis trial. Normalized activated protein C sensitivity ratio (nAPC-SR), clotting activity of factors V and VIII, and levels of protein C antigen were measured prior to and at days 3 and 7 after surgery. Bilateral venography was done in all patients at days 8-10 to demonstrate deep vein thrombosis. A lowered nAPC-SR was found in 76% (baseline), 80% (day 3), and 88% (day 7) of patients. It was inversely related to factor VIII clotting activity (p = .0003) and protein C antigen, ( p = .02). Deep vein thrombosis was demonstrated in 30% of pa tients with a normal nAPC-SR and in 23% of patients with a lowered nAPC-SR. Pulmonary embolism was not observed. Multivariate analysis did not identify a lowered nAPC-SR as a thrombotic risk factor, in contrast with gender (women, p = .02) and Quetelet index (≥25 kg/m2, p = .006). Our data provide no evidence that acquired activated protein C resis tance, frequently found in neurosurgical patients, contributes to their high risk of postoperative deep vein thrombosis.
State-of-the-Art Review : Aspirin Seems as Effective as Myelosuppressive Agents in the Prevention of Rethrombosis in Essential Thrombocythemia
Authors: Randi Maria Luigia , Rossi Carla , Fabris Fabrizio , Menapace Laura , Girolami Antonio
Published: November 2007

The course of essential thrombocythemia (ET) is complicated by bleeding, major thrombosis, and microvascular complications. Because about one-half of ET patients remain asymptomatic long term, the decision to use aspirin acetylsali cylic acid, (ASA) or myelotoxic drugs has not yet been clearly established. While vasomotor symptoms are improved by small doses of ASA, higher doses (900 mg/day) induce an unaccept able rate of serious hemorrhagic complications in patients with polycythemia vera. This retrospective study evaluates the util ity of therapy in preventing thrombosis in ET and the efficacy and a safety of 100 mg/day of ASA in these patients. One hundred ninety-five consecutive patients with ET diagnosed in agreement with the Polycythemia Vera Study Group (PVSG) criteria are evaluated. All vascular complication before, at, or after diagnosis were recorded and related to the treatment used: no therapy, ASA alone, myelosuppressive agents or both. All treated patients had a significant reduction of thrombotic com plications without increased hemorrhagic complications, in spite of therapy adopted. In addition, a significant reduction of rethrombosis was obtained in 60 patients with a previous thrombosis. A low rate of thrombosis (5.1 %) was observed during the follow-up of the 135 patients previously asymptom atic for major complications. No difference appears to exist between the use of ASA and cytotoxic drugs in preventing thrombosis and rethrombosis in ET patients. However, the pos sible increase of cancer and leukemia with myelosuppressive drugs is minimized in patients treated with ASA. A low dose of ASA would seem to be a safe and effective agent in ET.
Effects of Ticlopidine or Ticlopidine Plus Aspirin on Platelet Aggregation and ATP Release in Normal Volunteers: Why Aspirin Improves Ticlopidine Antiplatelet Activity
Authors: Altman Raul , Scazziota Alejandra , Rouvier Jorge , Gonzalez Claudio
Published: November 2007

Aspirin and ticlopidine are used to prevent arterial thrombosis. In some clinical settings ticlopidine is administered with aspirin for improving antithrombotic effect. We adminis tered aspirin (100 mg/day), ticlopidine (500mg/day), or ticlo pidine and aspirin for 7 days to healthy volunteers. Platelet aggregation and ATP release induced by sodium arachidonate, ADP, or a combination of both were measured. Sodium ara chidonate (0.25 mmol/L), which produces no platelet aggrega tion, combined with adenosine diphosphate (1 μmol/L), which produced a reversible platelet aggregation of 20% after ticlo pidine, resulted in a synergistic platelet aggregation response in normal (74.6 ± 9.2%) and in ticlopidine platelet-rich plasma (59.1% ± 14.9%, p < 0.0001). Synergism after sodium arachi donate (0.75 mmol/L) plus adenosine diphosphate (4 μmol/L) fell from 75.8% ± 11.0% and 59.1% ± 15.6% after ticlopidine or aspirin, respectively, to 14.8% ± 18.0% (p < 0.0001) after ticlopidine plus aspirin. Aspirin and ticlopidine alone did not inhibit adenosine triphosphate release as thoroughly as did as pirin plus ticlopidine. Aspirin or ticlopidine does not ad equately prevent platelet activity as ticlopidine plus aspirin do. Addition of aspirin to treatment with ticlopidine improves their antiplatelet activity and better results could be obtained in ar terial thrombotic prevention strategies.
Simultaneous Monitoring of Argatroban and Its Major Metabolite Using an HPLC Method: Potential Clinical Applications
Authors: Ahmad Sarfraz , Ahsan Ahmad , George Magdalena , Iqbal Omer , Jeske Walter P. , McKenna Rajalaxmi , Lewis Bruce E. , Walenga Jeanine M. , Fareed Jawed
Published: November 2007

Argatroban is a peptidomimetic inhibitor of throm bin that is currently undergoing extensive clinical trials as a heparin substitute for thrombotic complications. Argatroban is readily metabolized into a major derivative, M1, that has phar macological characteristics distinct from its parent compound. The currently available clot-based assays measure the cumula tive anticoagulant effect of argatroban and its metabolite(s). Available HPLC methods do not differentiate between argatro ban and M1-metabolite. A modified method was developed to simultaneously quantitate M1-metabolite and argatroban in biological fluids. Initial validation studies for the method in cluded clinical trials of argatroban in patients with heparin- induced thrombocytopenia, (ARG 911 Study) and coronary in terventional procedures (ARG 310 Study). Plasma samples were extracted with acetonitrile and reconstituted in a mobile phase. Calibration curves were prepared by running known standards of argatroban and M1-metabolite in normal human plasma. Ultraviolet detection was made at 320 nm. The reten tion times for argatroban and M1-metabolite peaks were found to be 10.5 ± 0.3 minutes and 3.9 ± 0.1 minutes, respectively. The extraction efficiency was > 95% (r2 = 0.99). In heparin- induced thrombocytopenia patients with major bleeding com plications (n = 30), the relative increase in M1-metabolite compared to argatroban varied widely (two- to eight-fold). The mean concentration of argatroban during the steady infusion period was found to be 0.7 ± 0.35 μg/mL, and for M1- metabolite, it was 5.5 ± 2.8 μg/mL. Proportionate results were not seen when higher dosages of argatroban were administered (coronary angioplasty studies). Argatroban and M1-metabolite levels also compared well with the results in global clotting assays. Owing to the simultaneous quantitation of argatroban and M1-metabolite, this method provides a rapid assessment of the pharmacokinetics and pharmacodynamics of argatroban. The differential quantitation may be useful in the assessment of relative metabolic turnover of argatroban that can be related to the hepatic and renal functions in a given patient.
Stability of mitomycin C in different infusion fluids: Compatibility with heparin and glucocorticosteroids
Authors: Dorr Robert T. , Liddil James D.
Published: November 2007

Introduction: Mitomycin C (Mutamycin) stability and compatibility was analyzed by reverse-phase high performance liquid chromatography (HPLC).

Methods: The drug was reconstituted in sterile water for injection USP, 0.9% sodium chloride for injection USP, 5% dextrose injection USP and lactated Ringer's injection USP. Samples were stored for vari ous times at —20°C, 4°C and 25°C in both glass and plastic (polyvinyl chloride) containers.

Results: Mitomycin C was shown to be stable (> 90% remaining for 5 to 7 days at room temperature in nondextrose containing infusion fluids. Greater stability was noted at drug concentrations ≥ 0.4 μg/mL and at reduced temperatures. In 5% dextrose solutions, stability was highly dependent upon pH: 3.4 hours at pH 4.7 and slightly over 24 hours at pH 5.5. Non-linear decomposition in dextrose was due to a slow increase in solution pH after adding mitomycin C. There were no stability differences for glass or plastic containers. Mitomycin was shown to be stable for prolonged periods when mixed with dexametha sone sodium phosphate (T90% > 2 days), with hydro cortisone sodium succinate (T90% > 7 days) or with sodium heparin (T90% > 2 days). Within these times, the concentrations of corticosteroids (measured by HPLC) and heparin (measured by bioassay) did not significantly decline.

Conclusions: Mitomycin C demonstrates pro longed stability in nonacidic infusion fluids. Long- term storage in dextrose-containing solutions should be avoided, but short-term admixture with heparin and corticosteroids is feasible.