Mutation screening for the prothrombin variant G20210A by melting point analysis with the Light Cycler system: atypical results, detection of the variant C20209T and possible clinical implications.

In the differential diagnosis of thrombophilic disorders genotyping of prothrombin and factor V are nowadays performed as a routine analysis. In the following we describe the unusual results of the mutation screening using melting point analysis for two patients and the consecutive detection of the mutation C20209T by sequencing the corresponding gene fragments. The molecular result is discussed with special respect to the medical history, ethnic background and clinical findings of both patients.

Should health-care systems pay for replacement therapy in patients with alpha(1)-antitrypsin deficiency? A critical review and cost-effectiveness analysis.

STUDY OBJECTIVES: Assess cost effectiveness for providing alpha(1)-antitrypsin (alpha(1)-AT) replacement therapy to individuals with severe COPD and alpha(1)-AT deficiency. MATERIALS AND METHODS: The electronic databases MEDLINE and EMBASE were searched, and relevant bibliographies were reviewed. Effect size, defined as the absolute risk difference between treated and untreated groups, was taken from the highest level of supporting evidence. The cost for providing alpha(1)-AT replacement therapy was analyzed from a payer perspective and was based on Medicare reimbursement rates. Effect size and costs were varied. The year of life saved was discounted up to 7%. RESULTS: The incremental cost per year of life saved for alpha(1)-AT replacement therapy (60 mg/kg/wk IV) in a 70-kg subject with severe alpha(1)-AT deficiency and an FEV(1) < 50% of predicted based on the National Institutes of Health (NIH) Registry mortality rate data is $13,971. The incremental cost depends substantially on the mortality rate reduction. When the effect size is altered from 10 to 70%, with the cost fixed at $52,000, the incremental cost per year of life saved ranges from $152,941 to $7,330. When effect size is 55% (as in the NIH Registry) but costs are increased almost 300%, from $52,000 to $150,000 per year, then the incremental cost per year of life saved increases from $13,971 to $40,301. CONCLUSION: No randomized, placebo-controlled trials are available to assess mortality rate reduction with alpha(1)-AT replacement therapy. The best currently available data are observational, from the NIH Registry. Based on these data, alpha(1)-AT replacement therapy is cost-effective in individuals who have severe alpha(1)-AT deficiency and severe COPD.

D-dimer assay predicts mortality in critically ill patients without disseminated intravascular coagulation or venous thromboembolic disease.

OBJECTIVE: To determine if D-dimer predicts outcomes in critically ill patients. DESIGN: Observational, cohort study. SETTING: Medical intensive care unit (MICU) of a tertiary care hospital. PATIENTS AND PARTICIPANTS: Seventy-four patients consecutively admitted to the MICU. INTERVENTIONS: D-dimer was measured by latex agglutination within 12 h of admission to the MICU. MEASUREMENTS AND RESULTS: Of the study population, 43.2% had positive D-dimers. The in-hospital mortality rate in D-dimer positive patients was 28.1% as compared to 7.1% in D-dimer negative subjects (p = 0.024). D-dimer positive patients had significantly greater frequencies of venous thromboses (21.9% vs 4.8%, p = 0.035). CONCLUSIONS: The D-dimer assay identifies patients at increased risk for mortality and may be a more sensitive test to determine the presence of underlying microvascular pathology in critically ill patients. A positive D-dimer at admission to the MICU is associated with an increased risk for the later development of a venous thromboembolic event (VTE).

Anaphylactoid reactions to methotrexate.

BACKGROUND: Methotrexate is a chemotherapeutic agent frequently utilized for the treatment of malignant, rheumatic, and pulmonary diseases. Although this agent has been extensively used for more than 45 years, there are few reports of immediate systemic hypersensitivity reactions. The reported immediate reactions include anaphylaxis, urticaria, and hepatitis. However, these reactions have been reported to occur only after some prior exposure to methotrexate. No immediate hypersensitivity reactions to methotrexate have been reported during the initial exposure. We describe two patients who developed immediate systemic hypersensitivity reactions during the initial administration of methotrexate. METHODS: The clinical outcomes of two patients treated by the Hematology/Oncology department at a tertiary care military medical center are described. The National Library of Medicine in Bethesda, Maryland, was electronically searched for the literature review. RESULTS: Patient 1, a 30-year-old male with localized high grade osteosarcoma of the left distal femur, developed generalized pruritus, urticaria, angioedema, and pharyngeal edema within 10 minutes of receiving the initial administration of intravenous high-dose methotrexate. No other pharmaceutical agents, such as antiemetics, were found to cause symptoms on rechallenge. The severity of this reaction precluded continuation of methotrexate therapy. Patient 2, a 23-year-old male with localized high grade osteosarcoma of the right distal tibia, developed pruritus and urticaria within 30 minutes of receiving the initial administration of intravenous high dose methotrexate. This patient, like most patients with immediate hypersensitivity reactions to methotrexate, developed recurrent symptoms during rechallenge of this agent despite prophylactic premedication. CONCLUSIONS: Unlike prior reports in our literature, our cases demonstrate that anaphylactoid reactions can occur during the initial exposure to methotrexate. Clinicians must be prepared to treat potentially life-threatening reactions with both the initial and subsequent doses of methotrexate.