Haemophilias A and B.
TL;DR: In the past, men with haemophilia were likely to die in their youth, but with advances in diagnosis, and especially with development of safe and effective treatment, affected individuals can now look forward to a normal life expectancy.
About: This article is published in The Lancet.The article was published on 2003-05-24. It has received 625 citations till now. The article focuses on the topics: Haemophilia & Haemophilia B.
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TL;DR: These evidence‐based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion‐transmitted infections.
Abstract: Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.
1,733 citations
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TL;DR: Thrombosis — localized clotting of the blood — can occur in the arterial or the venous circulation and has a major medical impact and is the most common cause of death in the developed world.
Abstract: Thrombosis — localized clotting of the blood — can occur in the arterial or the venous circulation and has a major medical impact. Acute arterial thrombosis is the proximal cause of most cases of myocardial infarction (heart attack) and of about 80% of strokes, collectively the most common cause of death in the developed world. Venous thromboembolism is the third leading cause of cardiovascular-associated death. The pathogenic changes that occur in the blood vessel wall and in the blood itself resulting in thrombosis are not fully understood. Understanding these processes is crucial for developing safer and more effective antithrombotic drugs.
960 citations
Cites background from "Haemophilias A and B."
...Humans deficient in factor VIII, factor IX or factor XI have mild haemostatic defects, whereas those deficient in factor XII have normal haemostasi...
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TL;DR: The results indicate that TF is essential for life, most likely because of its central role in hemostasis, and a nonhemostatic role of TF in the generation of coagulation proteases and subsequent activation of protease activated receptors (PARs) on vascular cells.
Abstract: Tissue factor (TF) is best known as the primary cellular initiator of blood coagulation. After vessel injury, the TF:FVIIa complex activates the coagulation protease cascade, which leads to fibrin deposition and activation of platelets. TF deficiency causes embryonic lethality in the mouse and there have been no reports of TF deficiency in humans. These results indicate that TF is essential for life, most likely because of its central role in hemostasis. In addition, aberrant TF expression within the vasculature initiates life-threatening thrombosis in various diseases, such as sepsis, atherosclerosis, and cancer. Finally, recent studies have revealed a nonhemostatic role of TF in the generation of coagulation proteases and subsequent activation of protease activated receptors (PARs) on vascular cells. This TF-dependent signaling contributes to a variety of biological processes, including inflammation, angiogenesis, metastasis, and cell migration. This review focuses on the roles of TF in hemostasis, thrombosis, and vascular development.
621 citations
TL;DR: Mortality from bleeding and its consequences, and from liver diseases and Hodgkin disease, was increased, but for ischemic heart disease it was lower, and for 14 other specific causes it did not differ significantly from general population rates.
479 citations
TL;DR: The roles of TF in protective hemostasis and pathological thrombosis are focused on and coagulation proteases, such as FVIIa, FXa, and thrombin are described.
Abstract: Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis TF is expressed on perivascular cells and epithelial cells at organ and body surfaces where it forms a hemostatic barrier TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart Under pathological conditions, TF can trigger both arterial and venous thrombosis For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture In sepsis, inducible TF expression on monocytes leads to disseminated intravascular coagulation In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute to venous thrombosis TF also has nonhemostatic roles For instance, TF-dependent activation of the coagulation cascade generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of protease-activated receptors This review will focus on the roles of TF in protective hemostasis and pathological thrombosis
384 citations
Cites background from "Haemophilias A and B."
...Hemophilia A and B patients are prone to spontaneous bleeding in the joints and skeletal muscle.(141) FXI deficiency is rare (1 per 100 000) and individuals with FXI deficiency rarely exhibit spontaneous bleeding but have an elevated risk of bleeding after surgery such as tooth extraction....
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References
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TL;DR: The sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease has been reported.
Abstract: To the Editor: We recently reported (April 18 issue)1 the sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease. These results have since been confirmed in four additional patients with typical X-linked severe combined immunodeficiency. Of the first four successfully treated patients, three continue to do well up to 3.6 years after gene therapy, whereas a serious adverse event occurred in the fourth patient. At a routine checkup 30 months after gene therapy, lymphocytosis consisting of a monoclonal population . . .
1,869 citations
TL;DR: Evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.
Abstract: Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.
1,051 citations
TL;DR: The complete 186,000 base-pair (bp) human factor VIII gene has been isolated and consists of 26 exons ranging in size from 69 to 3,106 bp and introns as large as 32.4 kilobases as mentioned in this paper.
Abstract: The complete 186,000 base-pair (bp) human factor VIII gene has been isolated and consists of 26 exons ranging in size from 69 to 3,106 bp and introns as large as 32.4 kilobases (kb). Nine kb of mRNA and protein-coding DNA has been sequenced and the mRNA termini have been mapped. The relationship between internal duplications in factor VIII and evolution of the gene is discussed.
988 citations
TL;DR: It appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.
Abstract: In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.
928 citations
TL;DR: Definitions in Hemophilia - Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX and the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.
Abstract: Definitions in Hemophilia - Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
797 citations