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Biomedical subjects

G M Rodgers

Publications and source records attributed to G M Rodgers.

At least 19 recordsLinked to original sources
PubMed2004

Polymorphisms in the 5'-UTR of the tissue factor gene are associated with altered expression in human endothelial cells.

BACKGROUND: Enhanced tissue factor (TF) expression mediates many disease processes. Recently, four completely concordant polymorphisms were detected in the 5'-UTR of the TF gene. Three were single base changes and one was an 18-bp insertion/deletion at -1208. OBJECTIVES: This study was undertaken to determine if the I-allele or the D-allele would associate with elevated TF expression in human umbilical vein endothelial cells (HUVEC). METHODS: HUVEC were genotyped by polymerase chain reaction for 18-bp insert status. TF expression was induced by interleukin (IL)-1 or phorbol 12-myristate 13-acetate (PMA). Total TF activity was determined by a one-stage clotting assay and surface TF activity by a chromogenic assay. Protein binding differences between the I- and D-alleles were examined by gel shift assays. RESULTS: IL-1- or PMA-induced total TF activity in D-allele HUVEC was increased 2.0-2.5-fold above that seen in II HUVEC. Surface clotting activity in D-allele cells was 1.3-1.7-fold greater than in II-allele cultures. Experiments with consensus site mutation oligos suggested that the 18-bp insert creates GATA and CCAAT-enhancer binding protein (C/EBP) transcription factor recognition sites. CONCLUSIONS: The D-allele is associated with enhanced TF activity in HUVEC. The differences in TF expression between the alleles may be due to variant transcription factor binding in the -1208 region. Further studies are warranted to investigate whether the D-allele is associated with increased incidence of pathological processes that involve TF.

5' Untranslated Regions↗
PubMed2001

Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.

BACKGROUND: Low-molecular-weight heparins administered subcutaneously once or twice daily have been reported to be as safe and efficacious as intravenous unfractionated heparin in the treatment of acute venous thromboembolic disease. OBJECTIVE: To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease. DESIGN: Randomized, controlled, partially blinded equivalence trial. SETTING: 74 hospitals in 16 countries. PATIENTS: 900 patients with symptomatic lower-extremity deep venous thrombosis, including 287 (32%) with confirmed pulmonary embolism. INTERVENTIONS: Initial therapy with dose-adjusted intravenous unfractionated heparin compared with subcutaneous enoxaparin at fixed dosages of 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Long-term oral anticoagulation was started in all patients within 72 hours of randomization. MEASUREMENTS: Clinical end points assessed during a 3-month follow-up period. RESULTS: Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once-daily enoxaparin and -1.2% (CI, -4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group. CONCLUSIONS: Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.

Administration, Cutaneous↗
PubMed2001

Update on selected inherited venous thrombotic disorders.

The inherited thrombophilias are a group of inherited conditions that predispose to thrombotic events. Most of the inherited thrombotic disorders are associated with venous thromboembolism rather than arterial thrombosis. Frequently, one or more predisposing genetic factors and/or environmental risk factor are identified in thrombosis patients. Significant advances in the identification of etiologies of inherited thrombosis have recently been reported. The most common inherited thrombotic disorders include activated protein C (APC) resistance (factor V Leiden), hyperhomocysteinemia, the prothrombin gene variant G20210A, elevated factor VIII levels, and deficiencies of thrombomodulin, protein C, protein S, and antithrombin. Less well characterized disorders include elevated factor IX, X, and XI levels. Recognition of these disorders now permits a laboratory diagnosis in approximately 70% of patients being evaluated for inherited thrombosis. This review focuses on the clinical and laboratory aspects of some of the most common inherited venous thrombotic disorders, including APC resistance, hyperhomocysteinemia, the prothrombin G20210A mutation, and elevated coagulation factor levels.

Blood Coagulation Factors↗
PubMed2001

Excessive anticoagulation in patients with mild renal insufficiency receiving long-term therapeutic enoxaparin.

Low-molecular-weight heparins, such as enoxaparin, are increasingly being used for treatment of venous thromboembolism. We describe two patients who received therapeutic enoxaparin for several months. Although their serum creatinine values were normal, both had mild renal insufficiency (creatinine clearance 60-70 ml/min), and both accumulated the drug abnormally and experienced clinical bleeding. These results suggest that patients receiving enoxaparin (or other low-molecular-weight heparins) in therapeutic doses for periods of more than 4 weeks should be considered for laboratory monitoring to avoid bleeding.

Adult↗
PubMed2001

Heparin-induced thrombocytopenia is rare in pregnancy.

OBJECTIVE: The indications for heparin use during pregnancy are expanding; however, heparin is associated with serious adverse effects including heparin-induced thrombocytopenia. Low-molecular-weight heparin is expensive but is associated with less frequent occurrences of heparin-induced thrombocytopenia in the nonpregnant population. However, the incidence of heparin-induced thrombocytopenia during pregnancy is unknown. The purpose of this study was to compare the incidence of heparin-induced thrombocytopenia in pregnant and nonpregnant women. STUDY DESIGN: This is a retrospective cohort comparison. Pregnant and nonpregnant women were identified by means of diagnosis related group and Current Procedural Terminology code searches at three medical centers in Utah; the incidence of heparin-induced thrombocytopenia in the two groups was compared. RESULTS: There were 10 (4%) cases of thrombocytopenia among 244 heparin-treated pregnant patients and 26 (11%) cases among the 244 nonpregnant controls. There were no cases of heparin-induced thrombocytopenia in the pregnant group, but there were 10 (4%) cases in the control group (P =.0014). CONCLUSION: Heparin-induced thrombocytopenia is extremely rare in pregnant women.

Adult↗
PubMed2001

Management of thrombosis in women with antiphospholipid syndrome.

1) Antiphospholipid antibody syndrome may be associated with unusual sites of thrombosis. 2) Laboratory evaluation involves testing for antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodies. 3) Acute management of thrombosis involves immediate anticoagulation. Low-molecular-weight heparins are as safe and effective as unfractionated heparin in this setting. Arterial events may require emergent thrombolytic therapy. Monitoring of the APTT with unfractionated heparin in the presence of a lupus anticoagulant is ineffective; these patients require monitoring of antifactor Xa levels or the use of LMWH, which does not require monitoring. 4) The pharmacokinetics of LMWH change in pregnancy, resulting in a shorter plasma half-life and larger volume of distribution. Monitoring of antifactor Xa levels is necessary. 5) Chronic anticoagulation is best achieved with warfarin, with significantly decreased rates of recurrent events when the INR is > or = 3.0. Long-term, if not life-long, anticoagulation is often necessary. Warfarin is teratogenic, and individuals desiring pregnancy will need to convert to therapeutic, not prophylactic, doses of either unfractionated heparin or LMWH. 6) As part of optimal management of thrombosis in APS, additional risk factors for thrombosis should be eliminated or reduced. These include comorbid illnesses such as hypertension and hyperlipidemia, as well as smoking. 7) Tamoxifen, raloxifene, oral contraceptives, and hormone replacement therapy are all associated with an increased risk of DVT in the general population. In APS patients receiving therapeutic anticoagulation, the addition of these drugs should not increase thrombosis risk. In APS patients not receiving anticoagulant therapy, these hormonal therapies may increase the thrombosis risk.

Acute Disease↗
PubMed2001

Discontinuation of the bleeding time test without detectable adverse clinical impact.

BACKGROUND: The bleeding time (BT) test predicts a higher bleeding complication rate in populations at risk for inherited or acquired platelet dysfunction, but it is of limited assistance in evaluating individual patients. There are no reports of clinical outcomes after discontinuation of the BT test. METHODS: Interviews with a subset of the physicians who had ordered the BT test before discontinuation of the test were conducted. The total number of platelet-aggregation tests, the mean number of monthly, unmodified platelet units transfused, the incidence of kidney biopsy complications, and the number of doses of 1-deamino-8-D-arginine vasopressin (DDAVP) administered 5 months before and after discontinuation of the BT test were compared. We recorded the rates of bleeding complications in the Major Surgery Risk Pool during the 12 months before and the 5 months after the discontinuation of the BT test. RESULTS: Clinicians reported they did not significantly change their preprocedural work-ups, postpone an invasive procedure, experience an increase in bleeding complications, or increase their use of blood products after discontinuation of the BT test. Platelet-aggregation tests (n = 9, before and after), platelet transfusions (P = 0.958), and DDAVP administration (before = 24; after = 10) did not increase after discontinuation of the BT test. The rate of postprocedural bleeding complications did not increase significantly in either Major Surgery Risk Pool cases (<3final sigma deviation from the mean rate) or in patients undergoing renal biopsies (P = 0.225 for decrease in hematocrit; P = 1.000 for the percentage of patients transfused) after discontinuation of the BT test. CONCLUSIONS: Our study failed to identify a clinically significant, negative impact of discontinuing the BT test.

Adult↗
PubMed2000

Evidence of increased angiogenesis in patients with acute myeloid leukemia.

Angiogenesis plays a key role in solid tumor growth. The purpose of this work was to study angiogenesis in acute myeloid leukemia (AML). We stained bone marrow samples from 20 adult patients with untreated AML and 20 normal controls using endothelial cell markers (ULEX-E and von Willebrand factor [vWF]). The number of vessels per millimeter length of bone marrow core biopsy specimen was scored by light microscopy. Using ULEX-E staining, AML marrows had (average +/- SEM) 8.3 +/- 3.6 vessels/mm (range, 3.7-19.3), whereas normal marrows had 4.3 +/- 1.8 vessels/mm (range, 1.6-7.9). A similar difference was noted using vWF staining (8.6 +/- 3.0 vessels/mm vs 4. 9 +/- 2.2 vessels/mm in AML vs normal bone marrows, respectively). The differences between the numbers of vessels/mm in AML and normal marrows were highly significant (P <.0001 for both ULEX-E and vWF staining). When analyzed by FAB category, there was no difference in the average number of vessels/mm among the different subgroups of AML. Using reverse transcriptase polymerase chain reaction, we observed that the HL-60 and U937 human AML cell lines and 4 of 4 freshly isolated AML cells from untreated patients expressed mRNA for vascular endothelial growth factor (VEGF). Both cell lines as well as all fresh AML isolates tested expressed VEGF protein. Basic fibroblast growth factor was expressed only in HL-60 cells and in only 3 of 4 fresh AML samples. These observations suggest that angiogenesis may play a role in the pathogenesis of AML. Inhibition of angiogenesis could constitute a novel strategy for the treatment of AML. (Blood. 2000;95:309-313).

Adult↗
PubMed2000

Detection of occult cobalamin deficiency by magnetic resonance imaging.

We present a case of cobalamin deficiency in an elderly woman who presented with peripheral neuropathy without evidence of anemia or macrocytosis; her diagnosis was suspected with cervical magnetic resonance imaging. This imaging modality may identify patients with cobalamin deficiency who have neurologic abnormalities with normal hematologic parameters.

Aged↗
PubMed2000

Utilization and outcomes of enoxaparin treatment for deep-vein thrombosis in a tertiary-care hospital.

The availability of a low-molecular-weight heparin, enoxaparin, to treat deep-vein thrombosis (DVT) offers the option for outpatient therapy for certain DVT patients. We monitored the utilization and outcomes of enoxaparin treatment for DVT in our tertiary-care hospital. A retrospective chart survey was performed for all DVT patients treated at our facility between October 1998 and September 1999. We tracked treatment received (unfractionated heparin or enoxaparin), clinical outcomes (recurrent thromboembolism or bleeding), and whether the patient would have met practice guideline criteria for outpatient enoxaparin therapy. A total of 266 patients were either admitted to the hospital for DVT or experienced DVT during their hospitalization. Of 266 DVT patients, 73 (27%) received enoxaparin. Sixty-four (88%) patients receiving enoxaparin met practice guideline criteria. Nine patients (12%) who did not meet criteria also received the drug. Major bleeding occurred in 3 patients (4%) receiving enoxaparin; one patient had a life-threatening hemorrhage. Two of the three patients with major bleeding had contraindications to enoxaparin use. Only 45% of our DVT patients were appropriate candidates for outpatient enoxaparin therapy. We conclude that in tertiary-care hospitals with acutely ill patients, most DVT patients will not be candidates for outpatient therapy with enoxaparin. Limitations to enoxaparin use are not widely appreciated.

Enoxaparin↗
PubMed1999

Immunosuppressive effects of factor IX products: an in vitro study.

The effects of a recombinant factor IX product (BeneFix), and of five plasma-derived factor IX products, AlphaNine, Immunine, Konyne, Mononine and Replinine on in vitro peripheral blood mononuclear cell (PBMC) immune function were compared in a blinded study. We assessed the effects of these products on Con-A-induced lymphocyte proliferation and interleukin-2 and interleukin-10 secretion, expression of lymphocyte activation markers, and nitric oxide secretion by stimulated mouse peritoneal macrophages. At 1 mL-1 for 48 h, Konyne reduced Con-A-induced mitogenesis by 50% (P < 0.05); AlphaNine, Mononine and BeneFix had no effect. At 10 IU mL-1, Con-A-induced mi- togenesis was at control levels with Mononine and BeneFix, but was reduced to <15% (P < 0.05) with each of the other products. IL-2 and IL-10 secretion by Con-A-stimulated lymphocytes was also markedly depressed by all the products tested except Mononine and BeneFix. Dialysis of these products did not substantially affect these results. Flow cytometric analysis of lymphocyte activation markers following Con-A stimulation showed that Konyne also decreased IL-2 receptor alpha and beta chain (CD25 and CD122) induction on PBMC. Konyne also inhibited nitric oxide secretion to levels <18% of controls. These results indicate that certain factor IX products, including some of purported higher purity, substantially depress in vitro immune function. The importance of these findings to in vivo immune function in haemophilia B patients remains to be established.

Animals↗
PubMed1999

Dithiocarbamates ameliorate the effects of endotoxin in a rabbit model of disseminated intravascular coagulation.

Induction of tissue factor (TF) activity by endotoxin and cytokines is an important mechanism for initiation of disseminated intravascular coagulation (DIC) seen in patients with gram-negative sepsis. Based on data from an in vitro study in which dithiocarbamates abrogated endothelial cell TF activity by inhibition of the NF-kappaB pathway, we investigated whether dithiocarbamates had in vivo activity in an animal model of DIC. Dithiocarbamates ameliorated the adverse clinical and histological effects of endotoxin-induced DIC, including morbidity, hypofibrinogenemia, and target organ damage, especially in the liver and kidney, even when given up to 1 hour after administration of endotoxin. This pilot study confirms the key role of the nuclear factor-kappa beta (NF-kappaB) pathway in induction of TF activity in initiating sepsis-associated DIC and suggests that dithiocarbamates may be useful in treatment of DIC associated with excessive TF expression because of gram-negative sepsis. Additional studies of dithiocarbamates in DIC models are warranted.

Animals↗