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1.  Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann’s thrombasthenia 
Glanzmann’s thrombasthenia (GT) is a congenital qualitative platelet disorders due to the deficiency or defect of platelet membrane GPIIb/IIIa (integrin αIIbβ3). The standard treatment for bleeding is platelet transfusion but repeated transfusion may result in the development of anti-platelet antibodies (to HLA and/or GPIIbIIIa) rendering future platelet transfusion ineffective. Alternative effective agent(s) are needed. There are increasing reports documenting efficacy of high dose rFVIIa in GT patients with adverse events uncommon. The efficacy is supported by evidence that high concentration FVIIa binds to activated platelet surface and improves thrombin generation to enhance deposition (adhesion) and aggregation of platelets lacking GPIIb/IIIa. While there are increasing clinical experiences, evidence-based clinical data are not available. There is a need for more clinical studies, particularly clinical trials, to further assess the efficacy, safety (particularly thrombotic events) and optimal regimen of rFVIIa in GT patients, either singly or in combination with other hemostatic agents such as platelet transfusion. In the absence of this data, for treatment of severe bleeding in GT patients with platelet antibodies and platelet refractoriness, rFVIIa at dose 90 μg/kg every 2 h for 3 or more doses could be considered. This more “optimal regimen” derived from a recent International Survey needs confirmation with larger studies. What the optimal regimen for surgical coverage is remains unresolved.
PMCID: PMC2291310  PMID: 18078017
Glanzmann’s thrombasthenia; recombinant human activated factor VII (rFVIIa); bleeding; surgery; platelet transfusion; GPIIb/IIIa
2.  Cross-cultural adaptation of the CHO-KLAT for boys with hemophilia in rural and urban china 
Background
Quality of life (QoL) is increasingly recognized as an important outcome measure in clinical trials. The Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT) shows promise for use in China.
Objective
To adapt the CHO-KLAT version 2.0 for use in clinical trials in China.
Methods
Forward and back translations of the CHO-KLAT2.0 were completed in 2008. Between October 2009 and June 2010, a series of 3 focus groups were held with 20 boys and 31 parents in rural and urban China to elicit additional concepts, important to their QoL, for the Chinese CHO-KLAT2.0. All of the items identified by boys and parents were reviewed by a group of experts, resulting in a Chinese version of the CHO-KLAT2.0. This version underwent a detailed cognitive debriefing process between October 2010 and June 2011. Thirteen patient-parent pairs participated in this cognitive debriefing process until a stable and clearly understood Chinese version of the CHO-KLAT2.0 was obtained.
Results
The initial back translation of the Chinese CHO-KLAT2.0 was slightly discrepant from the original English version on 12 items. These were all successfully adjudicated. The focus groups identified 9 new items that formed an add-on Socio-Economic Context (SEC) module for China. Linguistic improvements were made after the 2nd, 5th, 7th and 13th cognitive debriefings pairs and affected a total of 18 items. The result was a 35 item CHO-KLAT2.0 and a SEC module in Simplified Chinese, both of which have good content validity.
Conclusion
This detailed process proved to be extremely valuable in ensuring the items were accurately interpreted by Chinese boys with hemophilia ages ≤18 years. The need for the additional SEC module highlighted the different context that currently exists in China with regard to hemophilia care as compared to many Western countries, and will be important in tracking progress within both rural and urban China over time. Changes based on the cognitive debriefings suggest that expert verbatim translation alone is not sufficient. The Chinese version of the CHO-KLAT2.0 is well understood by boys with hemophilia in China. Next steps will be to test its construct validity and reliability in boys with hemophilia in China.
doi:10.1186/1477-7525-10-112
PMCID: PMC3499387  PMID: 22978454
Quality of life; Hemophilia; China; Children; Cross-cultural studies
3.  Mutations in the paralogous human α-globin genes yielding identical hemoglobin variants 
Annals of Hematology  2008;88(6):535-543.
The human α-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical α-globin chain. Over half of the α-globin structural variants reported to date are only characterized at the amino acid level. It is likely that a fraction of these variants, with phenotypes differing from one observation to another, may be due to the same mutation but on a different α-globin gene. There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes. Here, we report the results of a systematic multicenter study in a large multiethnic population to identify such variants and to analyze their differences from a functional and evolutionary perspective. We identified 14 different Hb variants resulting from identical mutations on either one of the two human α-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (α2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (α1) and that the α2/α1 ratio varied between variants. These α-globin chain variants have most likely occurred via recurrent mutations, gene conversion events, or both. Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-008-0624-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00277-008-0624-3
PMCID: PMC2690850  PMID: 18923834
α-Globin genes; Paralogues; Gene conversion; Hemoglobin variants; Mutations
4.  Immunofluorescent staining of lung biopsy in fibrosing alveolitis 
There is a group of lung diseases, as yet of unknown cause, which are characterized by a pathologic picture of alveolar wall fibrosis with an intra-alveolar exudate containing large cells. A case is reported with this clinicopathological picture in which immunofluorescent studies of the biopsied lung tissue revealed no tissue-bound immunoglobulins, complement component (β1 C) or fibrinogen. The literature on the immunofluorescent studies of biopsied lung tissue in this group of lung diseases is reviewed. The reports are scant and varied, making it impossible to conclude that autoallergic mechanisms are solely responsible as the pathogenetic mechanism in this group of lung diseases.
Images
PMCID: PMC1941252  PMID: 4570681
5.  2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema 
Background
We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.
Objective
To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010).
Methods
The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'angioédème héréditaire (RCAH) http://www.haecanada.com and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review.
Results
This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference.
Conclusions
Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.
doi:10.1186/1710-1492-6-24
PMCID: PMC2921362  PMID: 20667127
6.  Safety and effectiveness of point-of-care monitoring devices in patients on oral anticoagulant therapy: a meta-analysis 
Open Medicine  2007;1(3):e131-e146.
Background
Point-of-care devices (POCDs) for monitoring long-term oral anticoagulation therapy (OAT) may be a useful alternative to laboratory-based international normalized ratio [INR] testing and clinical management.
Purpose
To determine clinical outcomes of the use of POCDs for OAT management by performing a meta-analysis. Previous meta-analyses on POCDs have serious limitations.
Data sources
PubMed, the Cochrane Library, DIALOG, MEDLINE, EMBASE, BIOSIS Previews and PASCAL databases.
Study selection
Randomized controlled trials of patients on long-term OAT, comparing anticoagulation monitoring by POCD with laboratory INR testing and clinical management.
Data extraction
1) rates of major hemorrhage; 2) rates of major thromboembolic events; 3) percentage of time that the patient is maintained within the therapeutic range; 4) deaths. Outcomes were compared using a random-effects model. Summary measures of rates were determined. The quality of studies was assessed using the Jadad scale.
Data synthesis
Seventeen articles (16 studies) were included. Data analysis showed that POCD INR testing reduced the risk of major thromboembolic events (odds ratio [OR] = 0.51; 95% confidence interval [CI] 0.35–0.74), was associated with fewer deaths (OR = 0.58; 95% CI = 0.38–0.89), and resulted in better INR control compared with laboratory INR testing. No significant difference between the two management modalities with respect to odds ratios for major hemorrhage was found.
Limitations
Quality scores varied from 1 to 3 (out of a maximum of 5). Only 3 studies defined how thromboembolic events would be diagnosed, casting doubt on the accuracy of the reporting of thromboembolic events. The studies suggest that only 24% of patients are good candidates for self-testing and self-management. Compared with patients managed with laboratory-based monitoring, POCD patients underwent INR testing at a much higher frequency and received much more intensive education on OAT management.
Conclusions
The use of POCDs is safe and may be more effective than laboratory-based monitoring. However, most patients are not good candidates for self-testing and self-management. Patient education and frequency of testing may be the most important factors in successful PODC management. Definitive conclusions about the clinical benefits provided by self-testing and self-management require more rigorously designed trials.
PMCID: PMC3113217  PMID: 21673942

Results 1-6 (6)