Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial.

BACKGROUND: In some but not all studies, men with venous thrombosis had a higher risk of recurrence than women. Information on women with initial hormone-related thrombosis is scant. OBJECTIVE: We assessed the incidence of recurrent thrombosis by gender, and among women using exogenous hormones or pregnant/postpartum at the time of index thrombosis. PATIENTS/METHODS: A total of 508 men and women with one or more previous venous thrombosis episodes were observed while participating in a randomized trial of low-intensity warfarin or placebo for 2.1 years. Index thrombosis events during treatment with postmenopausal hormones, oral contraceptives, or during pregnancy, or the puerperium were considered to be hormone-related events. RESULTS: Among 268 men the 3-year probability of recurrent thrombosis was 18.4% (95% confidence intervals; CI 12.3-24.4). Among 109 women without hormone-related thrombosis, the rate was 15.0% (95% CI 6.3-23.8). Among 129 women with hormone-related thrombosis, the rate was 5.0% (95% CI 1.1-8.9). Adjusting for other risk factors and treatment assignment, women had a 39% lower thrombosis recurrence risk than men: hazard ratio (HR) 0.61 (95% CI 0.34-1.08). Women with hormone-related thrombosis had a 58% lower risk than men: HR 0.42 (95% CI 0.19-0.97); and a 46% lower recurrence risk than other women; HR 0.54 (95% CI 0.19-1.54). Women without hormone-related index events had a recurrence rate similar to men; HR 0.83 (95% CI 0.42-1.66). CONCLUSIONS: In this trial population, women had a lower risk of recurrent venous thrombosis than men. This difference was explained by a low risk of recurrence among women with hormone-related index thrombosis.

Heparin-induced thrombocytopenia: natural history, diagnosis, and management.

Heparin-induced thrombocytopenia (HIT) is an under-recognized, limb- and life-threatening complication of pharmacologic heparin administration. Antibody formation against heparin complexed to platelet factor 4 (PF4) is central to the pathogenesis of HIT. Heparin:PF4 antibodies promote platelet activation and aggregation as well as excess thrombin generation which may lead to clinical thrombosis. HIT should be suspected in patients who develop thrombocytopenia with or without associated arterial or venous thrombosis while on heparin. HIT is a clinical diagnosis. Specialized HIT assays should be interpreted with care. The cornerstone of HIT management is the discontinuation of all forms of heparin exposure and the institution of anticoagulation with an alternative agent. The direct thrombin inhibitors lepirudin and argatroban are currently available and approved for use in patients with HIT.

Hypercoagulable syndromes: evaluation and management strategies for acute limb ischemia.

Acute limb ischemia secondary to peripheral arterial thrombosis is a relatively uncommon but ominous form of vascular accident. Select inherited and acquired hypercoagulable states appear to contribute to an initial arterial thrombosis and, more importantly, recurrent thrombotic events. Mounting interest in hypercoagulability, the increased availability of hypercoagulable state "profiles," and enhanced ability to identify an abnormality in tested patients have promoted widespread testing. Unfortunately, widespread testing has had a limited beneficial impact on the management of acute limb ischemia. Ideally, costly and specialized testing should be limited to situations in which the results will have a tangible impact on patient care. Clear goals of testing should be determined before testing is performed. This article addresses a practical approach to hypercoagulable state testing in patients with acute limb ischemia with a focus on abnormalities that impact patient management.

Potential clinical efficacy and cost benefit of a transesophageal echocardiography-guided low-molecular-weight heparin (enoxaparin) approach to antithrombotic therapy in patients undergoing immediate cardioversion from atrial fibrillation.

An alternative clinical management strategy and cost analysis model is presented for patients with atrial fibrillation of >2 days' duration who may benefit from immediate cardioversion with self-administered low-molecular-weight heparin (enoxaparin) as a bridge antithrombotic therapy to warfarin, after a negative transesophageal echo-cardiography (TEE) screening for thrombus. Assuming no difference in stroke or bleeding rates, our cost minimization model shows that the TEE-guided enoxaparin treatment costs are $1353 lower per patient than an intravenous unfractionated heparin approach. Sensitivity analyses for stroke and bleeding reveal that the treatment-cost economic dominance of the TEE-guided enoxaparin approach may be enhanced by an expected improvement in clinical outcome.

Demystifying two common genetic predispositions to venous thrombosis.

Two recently discovered genetic abnormalities substantially increase the risk of venous thromboembolism. Yet we do not advocate screening for these abnormalities except in cases in which the information gained would affect the course of action.

Plastic bronchitis occurring late after the Fontan procedure: treatment with aerosolized urokinase.

OBJECTIVE: To describe the use of aerosolized urokinase in a patient with plastic bronchitis after a Fontan procedure. DESIGN: Case report. SETTING: Pediatric intensive care unit in a university-affiliated children's hospital. PATIENTS: Report of one patient with acute respiratory failure secondary to plastic bronchitis. INTERVENTIONS: Aerosolized urokinase, multiple bronchoscopies, corticosteroids, mucolytics, bronchodilators, and atrial pacing. MEASUREMENTS AND MAIN RESULTS: Airway obstruction secondary to recurring casts improved with the treatments. Histologic analysis of the casts demonstrated less fibrin after treatments with aerosolized urokinase. No adverse events were noted. CONCLUSIONS: The addition of aerosolized urokinase to this patient's treatment regimen helped to resolve life-threatening airway obstruction secondary to fibrin casts.

Transesophageal echocardiography guided enoxaparin antithrombotic strategy for cardioversion of atrial fibrillation: the ACUTE II pilot study.

BACKGROUND: Patients with atrial fibrillation >2 days' duration for whom immediate cardioversion is desired or required are commonly hospitalized for 4 or more days of antithrombotic therapy with intravenous unfractionated heparin and commencement of oral warfarin. For these early cardioversion patients, self-administered low-molecular-weight heparin (enoxaparin sodium) as "bridge" therapy to warfarin may obviate the need for hospitalization and activated partial thromboplastin time monitoring and thus potentially lower costs and enhance utility. OBJECTIVE: To compare feasibility and safety of a transesophageal echocardiography (TEE)-guided enoxaparin strategy with those of a TEE-guided unfractionated heparin strategy in patients with atrial fibrillation of >2 days' duration undergoing early electrical or chemical cardioversion. DESIGN AND SETTING: This is a randomized, multicenter clinical trial at 11 hospitals in the United States. PATIENTS AND INTERVENTION: Two hundred patients with atrial fibrillation >2 days' duration requiring early chemical or electric cardioversion will be enrolled. TEE-guided intravenous unfractionated heparin bridge therapy will be compared with TEE-guided subcutaneous enoxaparin bridge therapy. OUTCOME MEASURES: Feasibility outcomes are time to hospital discharge, patient quality of life/utility, treatment costs, and sinus rhythm. Safety outcomes are ischemic stroke, transient ischemic attack, systemic embolization, major and minor bleeding, clinical hemodynamic instability, and cardiac and cardioversion-related death for a 5-week period from enrollment. CLINICAL IMPLICATIONS: The results of this pilot study will have important clinical and economic implications for the antithrombotic management of patients with atrial fibrillation undergoing TEE-guided cardioversion.

Overview of enoxaparin in the treatment of deep vein thrombosis.

Standard medical treatment for patients with acute venous thrombosis is antithrombotic therapy. Following a historical overview of the evolution of heparin therapy to include low-molecular weight heparin (LMWH), the pharmacokinetic properties of enoxaparin are described. Therapeutic advantages of LMWH over unfractionated heparin (UFH) are also discussed, including once- or twice-daily subcutaneous dosing, reduced hospital stays, elimination of therapeutic monitoring for most patients, and possibly less bone density loss. Studies have demonstrated that enoxaparin is at least equivalent to UFH with regard to efficacy and safety. Opportunities for future study include evaluation of enoxaparin's efficacy for the prevention of deep vein thrombosis within high-risk groups and for the treatment of thrombosis in such conditions as pregnancy, cancer, obesity, and renal insufficiency, and in children.

Stability and sterility of a recombinant factor VIII concentrate prepared for continuous infusion administration.

Minipumps may facilitate cost-effective and convenient continuous infusion (CI) therapy for severe hemophilia A. This study evaluated the in vitro sterility, ability to support bacterial growth, and specific activity stability of a recombinant factor VIII (FVIII; Bioclate, Centeon) delivered by simulated CI at a variety of temperatures and after the addition of heparin or antibiotic. Closed system CIs of Bioclate (89.5 IU/ml) with and without heparin were sampled and cultured over a 6 day period. Bioclate (53.7 IU/ml) with and without heparin or vancomycin was inoculated with 102-105 CFU/ml of S. aureus, S. epidermidis, Escherichia coli, E. cloacae, or Y. enterocolitica and assessed by quantitative culture after 1 and 3 days. The stability of Bioclate (50, 100, and 250 IU/ml) at three temperatures (21 degrees C, 37 degrees C, and 39 degrees C) with and without heparin or vancomycin was tested over a period of 28 days. FVIII activity was measured in triplicate by a chromogenic assay (Coamatic Factor VIII, Chromogenix) and purity evaluated by Western blot. No bacterial growth was detected during CI of FVIII for up to 6 days. Following bacterial inoculation, there was rapid growth (>3 log increase) of all tested bacterial species except S. aureus which only displayed a 1 log expansion at 3 days. The addition of heparin containing 9.45 microg/U benzyl alcohol had no effect on bacterial growth. The addition of vancomycin caused a modest suppression of S. aureus growth but not of E. coli. Diluent alone did not support bacterial growth. Neither concentration, increased temperature, nor the addition of heparin or vancomycin had a significant effect on FVIII activity stability. Samples retained >75% baseline activity for between 3 and 7 days, except the infusion of Bioclate 50 IU/ml plus heparin maintained at 21 degrees C which remained stable for 28 days. Western blot analysis supported the activity assay findings. Standard and concentrated preparations of Bioclate are suitable for CI when delivered by the MiniMed 404-SP minipump. Because of the observed nutritive capability of this FVIII concentrate for sustaining bacterial growth, any contamination could result in systemic infection.

Graduate surgical trainee attitudes toward postoperative thromboprophylaxis.

BACKGROUND: Postoperative deep vein thrombosis (DVT) results in significant morbidity and mortality. Appropriate patient risk assessment and proper use of prophylactic measures is crucial. METHODS: We conducted a confidential survey of general surgery house staff. The survey addressed DVT risk factor recognition, proximal and distal DVT absolute risk estimation, DVT prophylaxis strategies, and vena cava filter and low-molecular-weight heparin (LMWH) use. RESULTS: Obesity, immobility, malignancy, and previous DVT were overwhelmingly recognized as risk factors. Age >40, recent myocardial infarction, lupus anticoagulant, varicose veins, and factor V Leiden were inadequately recognized as risks. Deep vein thrombosis risk in the setting of cancer was underestimated. Most selected appropriate prophylactic strategies; many misunderstood vena cava filter and LMWH indications. CONCLUSIONS: We have identified specific areas of misunderstanding about DVT risk and prophylaxis that, if appropriately addressed during educational sessions, will enable young surgeons to make safer and more effective future decisions regarding thromboprophylaxis.

How to use low-molecular weight heparin for outpatient management of deep vein thrombosis.

Low-molecular weight heparins can be used to treat acute deep vein thrombosis on an outpatient basis, but such use requires careful planning and patient education. We present an algorithm used at the Cleveland Clinic.

Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss.

OBJECTIVE: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associated with an increased risk of venous, arterial, and placental thrombosis and recurrent pregnancy loss (RPL). Factor V Leiden (a point mutation [1691G-->A] in the factor V gene), the prothrombin 20210G-->A mutation, and homozygosity for a common polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene (677C-->T) have been associated with arterial and venous thrombosis and arterial occlusive disease. We explored an association between these markers of thrombophilic states and RPL. DESIGN: Prospective case-control evaluation. SETTING: University-associated private practice. PATIENT(S): Fifty nonpregnant women with three or more pregnancy losses and 50 healthy, nonpregnant controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Anticardiolipin and antiphosphatidylserine antibodies were detected in serum by ELISA. Polymerase chain reaction was performed to identify the factor V Leiden (1691G-->A) mutation, the thermobile MTHFR (677C-->T) mutation, and the prothrombin 20210G-->A mutation. RESULT(S): The following were identified by restriction fragment-linked polymorphism analyses: 1 (2%) factor V Leiden heterozygosity; 1 (2%) prothrombin 20210G-->A heterozygosity; and 4 (8%) thermolabile MTHFR homozygosity. None of these mutation frequencies in women with RPL were statistically significantly different from controls. CONCLUSION(S): These data suggest that factor V Leiden, thermolabile MTHFR (677C-->T), and prothrombin 20210G-->A are not found at an increased frequency in women with a history of early RPL.

Intranasal DDAVP induced increases in plasma von Willebrand factor alter the pharmacokinetics of high-purity factor VIII concentrates in severe haemophilia A patients.

Because native circulating factor VIII (FVIII) is maximally stabilized when it is bound to von Willebrand factor (vWf), increased plasma vWf levels may enhance the infused FVIII concentrate intravascular survival and efficacy in severe haemophiliacs. To assess whether the kinetic characteristics and recovery of high purity, plasma-derived (Monoclate-P, Centeon) and recombinant (Bioclate , Centeon) FVIII concentrates are enhanced by increased plasma vWf concentrations, we compared the pharmacokinetic response to a bolus of FVIII infused alone with the response to a bolus infused 2 h after the intranasal delivery of 300 microg of desmopressin acetate (DDAVP) High Concentration Nasal Spray (Stimate, Centeon) in 10 adult severe haemophiliacs. FVIII activity was determined using a one-stage clotting assay on cryopreserved plasma specimens obtained at baseline and at 14 distinct time points (0.25-48 h) following the FVIII infusions. Ristocetin co-factor activity (RCoFA) and vWf antigen levels were assayed at baseline and 2 h after Stimate. FVIII kinetic parameters were calculated using standard, noncompartmental kinetic methods. Statistical analysis was performed using a paired t-test with 95% confidence limits. The mean rises in RCoFA (0.65+/-0.44 IU mL(-1)) and vWf antigen (0.19+/-0.07 IU mL-1) induced by Stimate were significant (P<0.01 and P<0.0001, respectively). The mean increases in the volume of distribution at steady state (Vss) (13.2+/-9.3 dL) and mean residence time (MRT) (4.4+/-3.9 h) between the FVIII-only arm and the FVIII plus Stimate arm were highly significant (P = 0.0015 and P = 0. 0059, respectively). The mean differences in recovery, area under the curve (AUC), half-life, and clearance (Cl) were not significantly altered. Subgroup analysis revealed statistically significant increases in Vss and MRT (P = 0.025 and P = 0.012, respectively) following the administration of intranasal DDAVP in the Monoclate-P cohort, but not in the Bioclate group. These data suggest that even modest pharmacologically induced increases in plasma vWf can favourably affect the kinetics of high-purity, plasma-derived FVIII concentrates in severe haemophiliacs.

Factor V Leiden and other hypercoagulable state mutations are not associated with osteonecrosis during or after treatment for pediatric malignancy.

OBJECTIVE: Osteonecrosis (ON) is a debilitating complication of cancer treatment in children and is usually associated with systemic steroid therapy. Defects of coagulation may be important in the pathogenesis of ON. This study evaluated the prevalence of factor V Leiden (FVL, 1691G-->A), the most common inherited thrombophilic state, the prothrombin 20210G-->A polymorphism, and the thermolabile methylene tetrahydrofolate reductase (MTHFR, 677C-->T) variant in a group of children in whom ON developed during or after treatment for cancer. STUDY DESIGN: Children in whom ON developed during cancer treatment at St Jude Children's Research Hospital were studied (n = 24). Genomic DNA was isolated, and polymerase chain reaction was performed to identify the FVL, prothrombin 20210, and thermolabile MTHFR mutations. RESULTS: Sixteen of 24 patients had acute lymphoblastic leukemia. The mean age at ON diagnosis was 14.4 +/- 3. 7 years. The mean interval between cancer diagnosis and ON diagnosis was 27 +/- 21 months. Twenty-two patients had received steroids for a mean duration of 24 +/- 15 weeks before having development of ON. No patient had a history of thrombosis. Five (21%) patients had a family history of thrombosis. Genetic analysis revealed 0 (0%) of 24 FVL, 1 (4.5%) of 22 prothrombin 20210, and 3 (13.6%) of 22 thermolabile MTHFR. None of these mutation frequencies was significantly different from our control frequencies or published values. CONCLUSIONS: Although procoagulant abnormalities in general and FVL in particular have been detected in a significant number of patients with ON of the jaw and Legg-Perthes disease, we did not identify an increased prevalence of FVL or other hypercoagulable state mutations in a cohort of children with ON that developed during or after treatment for a variety of cancers.

Recognition, diagnosis, and management of heparin-induced thrombocytopenia and thrombosis.

This case report describes a post-coronary artery bypass graft patient who developed arterial thrombosis and loss of a dominant hand as a result of the common and serious immune complication of heparin anticoagulation, heparin-induced thrombocytopenia and thrombosis. This report underscores the need for all surgeons who use heparin in the course of their practice to be aware of heparin-induced thrombocytopenia and the spectrum of its clinical presentations and management. Thrombocytopenia or thrombosis that occurs in a patient receiving heparin should prompt a surgeon to stop all heparin as soon as possible and seek appropriate hematologic consultation. Because heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis are mainly clinical diagnoses, one should not wait for objective test confirmation of heparin-induced thrombocytopenia before stopping all heparin treatment. Alternative anticoagulation, other than low molecular weight heparin, must be considered for the patient who develops either condition. For surgeons who perform hand surgery, it is necessary to be aware of the significance of upper extremity thrombosis in a patient who is receiving heparin when consulted for surgical management.

Effect of intermediate- and high-purity factor VIII concentrates on immune function in HIV-seropositive haemophiliacs as assessed by quantitative CD 4 counts.

Intermediate-purity factor VIII (FVIII) concentrates are believed to adversely influence cellular immune function and accelerate HIV progression in haemophiliac patients. There are reports that cellular immunity, as measured by serial CD4 lymphocyte counts, is better preserved in HIV-infected haemophiliacs who receive high-purity concentrates compared with those receiving intermediate- or low-purity products. We retrospectively evaluated the rate of CD4 cell count decrease in 44 asymptomatic HIV-seropositive severe haemophilia A patients whose purity of prescribed FVIII concentrate was primarily determined by State of residence. Prior to January 1989 all study subjects received treatment with intermediate- or low-purity products. In January 1989 the patients from Mississippi (n = 15) began to exclusively receive a high-purity, monoclonal antibody purified, plasma-derived product from their State Department of Health. The Mississippi cohort was subsequently converted to a high-purity, recombinant FVIII product in May 1993. Patients from Tennessee and Arkansas (n = 29) received intermediate-purity factor during the entire analysis period. Patients were monitored for an average of 68 months with an average of 11 CD4 cell count measurements. The rate of CD4 cell count decrease was derived from the calculated slope of a simple regression in order to account for large individual CD4 count fluctuations during the study period. There was no statistically significant difference in starting CD4 cell count between the 2 study groups. The rate of CD4 cell count decrease was 21.8 ± 52.9 cells µL(-1) year(-1) and 17.0 ± 32.6 cells µL(-1) year(-1) in the high-purity FVIII group and inter-mediate-purity FVIII group, respectively (P = 0.83). The difference in rate of CD4:CD8 ratio decrease between the two groups was also not statistically significant (P = 0.41). These data suggest that the use of the more costly, high-purity monoclonal antibody purified and recombinant FVIII concentrates does not influence the rate of decrease in CD4 cell count in HIV-seropositive haemophiliacs compared with concentrates of lower specific activity obtained using standard chromatographic techniques.

Acquired free protein S deficiency associated with multiple myeloma: a case report.

Investigation of recurrent venous thromboembolic events in a 46-year-old man with progressive IgG kappa (total serum IgG, 74.3 mg/ml) multiple myeloma revealed profound reductions in free protein S (PS) antigen (<0.l U/ml) and PS activity (0.33 U/ml). Total PS antigen, protein C, antithrombin III, and C4b-binding protein levels were within normal limits. The patient had no family history suggestive of a congenital PS deficiency and no history of thrombosis predating the diagnosis of his plasma cell dyscrasia. Patient IgG was isolated from serum using a protein A-sepharose affinity column and characterized. PS-dependent clotting assays (Staclot Protein S, Diagnostica Stago, Asnieres sur-Seine, France) performed on normal pooled plasma mixed with dilutions of patient IgG (0.0-33.0 mg/ml) revealed a dose-dependent neutralization of PS activity by 43%. Total and free PS antigen levels were measured using Laurell rocket electroimmunodiffusion (Assera-Plate Protein S, Diagnostica Stago), which revealed a similar dose-dependent reduction in free PS antigen but preserved normal total PS antigen. Free PS antigen was reduced by 77% to 0.23 U/ml using an IgG concentration (16.5 mg/ml) less than one-fourth of that of the patient at time of serum collection. Specific binding of the patient IgG to commercially available purified human PS was demonstrated by Western immunoblot analysis. Whereas acquired free PS deficiency has been previously reported in association with nephrotic syndrome, inflammatory bowel disease, HIV infection, and varicella infection, this is the first reported case of a hypercoagulable syndrome associated with acquired free PS deficiency and multiple myeloma.

In vitro characterization of high purity factor IX concentrates for the treatment of hemophilia B.

This study employed sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis and immunoblotting to assess the purity of seven high purity factor IX concentrates: Aimafix (Aima), AlphaNine-SD (Alpha Therapeutic), Factor IX VHP (Biotransfusion), Immunine (Immuno), Mononine (Armour Pharmaceutical), Nanotiv (Kabi Pharmacia), and 9MC (Blood Products Laboratory). The mean specific activity of these products ranged from 68 U factor IX/mg (Aimafix) to 246 U factor IX/mg (Mononine). SDS-PAGE analysis showed that the highest purity product, Mononine, had a single contaminating band under non-reducing conditions. Two additional bands were detected when this product was analyzed under reducing conditions. All other products had multiple contaminating bands that were more apparent under reducing than non-reducing conditions. The immunoblot for factor IX showed a dominant factor IX band for all products. In addition, visible light chain of factor IX was detected for AlphaNine-SD, Factor IX VHP, Immunine, Mononine, Nanotiv, and 9MC, suggesting that the factor IX in these products had undergone partial activation to factor IXa. Another contaminating band was visible at 49,500 for all of the products except 9MC. In addition to this band, high molecular weight contaminants were apparent for some products, most notably AlphaNine-SD. The identity of these bands is unknown. Immunoblotting failed to demonstrate factor VII as a contaminant of any of the high purity products, although factor VIIa could be detected in some lots of Immunine, Nanotiv, and 9MC by a clot-based assay. Factor X contaminated Aimafix, AlphaNine-SD, Factor IX VHP, Immunine, Nanotiv, and 9MC, but activation products of factor X were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)