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Medicine Jan 1997Considerable progress has been made in characterizing the specific molecular defects responsible for the heterogeneous disorder known as von Willebrand disease (VWD). A... (Review)
Review
Considerable progress has been made in characterizing the specific molecular defects responsible for the heterogeneous disorder known as von Willebrand disease (VWD). A large number of molecular defects have been identified and precise characterization may now be possible in the majority of type 2A, type 2B, type 2N, and potentially also type 3 VWD cases. However, the most common variant, type 1 VWD, still remains a major challenge. Continued progress in this area will improve our understanding of the pathogenesis of VWD and lead to more rapid and precise diagnosis and classification for this common disorder. The problems of incomplete VWD penetrance and poor diagnostic sensitivity and accuracy for the currently available clinical laboratory tests provide strong incentives for the development of DNA-based diagnostics. In addition, prenatal diagnosis is now possible either at the level of single point mutations (for some subtypes) or by RFLP analysis (assuming linkage to the von Willebrand factor [VWF] gene) and will probably be applied with increasing frequency for VWD type 3 (17, 133, 175). Understanding the molecular basis of VWD also has important implications for VWF structure and function and is helping to define critical binding domains within the VWF molecule. Insights gained from these studies may eventually lead to improved therapeutic approaches not only for VWD, but also for a variety of other genetic and acquired hemorrhagic and thrombotic disorders.
Topics: DNA Probes; Hemorrhage; Humans; Molecular Biology; Point Mutation; Polymorphism, Restriction Fragment Length; Prenatal Diagnosis; Thrombosis; von Willebrand Diseases; von Willebrand Factor
PubMed: 9064484
DOI: 10.1097/00005792-199701000-00001 -
The Pan African Medical Journal 2017
Topics: Female; Hemorrhagic Disorders; Humans; Infant, Newborn; Male; Vitamin K; Vitamin K Deficiency Bleeding
PubMed: 29541298
DOI: 10.11604/pamj.2017.28.150.13159 -
Polish Archives of Internal Medicine Mar 2020Von Willebrand disease (VWD) is the most common congenital bleeding disorder, with a clinical presentation of mucocutaneous and surgical bleeding varying from mild to... (Review)
Review
Von Willebrand disease (VWD) is the most common congenital bleeding disorder, with a clinical presentation of mucocutaneous and surgical bleeding varying from mild to severe. It is inherited in an autosomal dominant or autosomal recessive manner. The disease is caused by quantitative or qualitative deficiency of the von Willebrand factor (VWF) and is classified as type 1, 2 (2A, 2B, 2M, 2N), and 3. Although type 1 VWD is the most common form of VWD, the f ormal cutoff for diagnosis remains a subject of debate. In our paper, we present results of studies regarding the clinical and laboratory importance of a new type of bleeding disorder called low VWF. The new guidelines for VWD diagnosis and management suggested that patients with historically type 1 VWD should be divided into 2 subsets: type 1 VWD with a VWF antigen level (VWF:Ag) of less than 30 IU/dl or less than 40 IU/dl, in which about 80% of patients exhibited VWF gene mutations, and low VWF with a VWF:Ag level of 30 to 50 IU/dl or 40 to 50 IU/dl, in which the causative mutation is detected in merely 40% of patients and in most families, inheritance is not dependent on the locus of VWF on chromosome 12. Previously, moderately reduced VWF levels (30-50 IU/dl) were considered a risk factor for bleeding, but not a true bleeding disorder, and this condition was named low VWF. Recently, it was documented in a large group of patients with type 1 VWD and low VWF that bleeding score does not correlate with VWF:Ag and bleeding symptoms in type 1 VWD (<30 IU/dl) and low VWF can change from infrequent and moderate to severe bleeds. Because the plasma concentration of VWF depends on many physiological and pathological factors that may mask the diagnosis of VWD, separation of the group of patients with low VWF (30-50 IU/dl) from those with type 1 VWD may delay or prevent them from receiving appropriate treatment. Diagnosis of VWD in each case, particularly those with a slight decrease in VWF (30-50 IU/dl), should be based primarily on the clinical manifestations and family history of hemorrhagic diathesis.
Topics: Disease Management; Female; Humans; Male; Mutation; von Willebrand Disease, Type 1; von Willebrand Diseases; von Willebrand Factor
PubMed: 31990275
DOI: 10.20452/pamw.15162 -
Blood Nov 1946
Topics: Disease Susceptibility; Hemorrhagic Disorders; von Willebrand Diseases
PubMed: 21002320
DOI: No ID Found -
Journal of Thrombosis and Haemostasis :... Sep 2010
Topics: Hematology; Hemorrhage; Hemorrhagic Disorders; Humans; Reproducibility of Results; Severity of Illness Index; Surveys and Questionnaires; von Willebrand Diseases
PubMed: 20626619
DOI: 10.1111/j.1538-7836.2010.03975.x -
Journal of Leukocyte Biology Nov 2016Ebola viruses (EBOVs) and Marburg viruses (MARVs) are among the deadliest human viruses, as highlighted by the recent and widespread Ebola virus outbreak in West Africa,... (Review)
Review
Ebola viruses (EBOVs) and Marburg viruses (MARVs) are among the deadliest human viruses, as highlighted by the recent and widespread Ebola virus outbreak in West Africa, which was the largest and longest epidemic of Ebola virus disease (EVD) in history, resulting in significant loss of life and disruptions across multiple continents. Although the number of cases has nearly reached its nadir, a recent cluster of 5 cases in Guinea on March 17, 2016, has extended the enhanced surveillance period to June 15, 2016. New, enhanced 90-d surveillance windows replaced the 42-d surveillance window to ensure the rapid detection of new cases that may arise from a missed transmission chain, reintroduction from an animal reservoir, or more important, reemergence of the virus that has persisted in an EVD survivor. In this review, we summarize our current understanding of EBOV pathogenesis, describe vaccine and therapeutic candidates in clinical trials, and discuss mechanisms of viral persistence and long-term health sequelae for EVD survivors.
Topics: Africa, Western; Animals; Antiviral Agents; Body Fluids; Capillary Permeability; Clinical Trials as Topic; Communicable Diseases, Emerging; Disease Models, Animal; Disease Outbreaks; Disease Reservoirs; Ebola Vaccines; Ebolavirus; Gene Expression Regulation, Viral; Hemorrhagic Disorders; Hemorrhagic Fever, Ebola; Host Specificity; Humans; Immunity, Innate; Lymphopenia; Multicenter Studies as Topic; Organ Specificity; Population Surveillance; Species Specificity; Virulence; Virus Latency
PubMed: 27587404
DOI: 10.1189/jlb.4RI0316-099RR -
Blood Mar 2015Despite the worldwide prevalence of rare bleeding disorders (RBDs), knowledge of these conditions and their management is suboptimal; health care professionals often... (Review)
Review
Despite the worldwide prevalence of rare bleeding disorders (RBDs), knowledge of these conditions and their management is suboptimal; health care professionals often have little diagnostic and treatment experience with variable access to diagnostic modalities required for accurate identification. Therefore, patients often experience morbidity and mortality due to delayed diagnosis. As RBDs represent a small potential commercial market, few, if any, specific therapies exist for these conditions. As a result, affected individuals commonly face delayed diagnosis, incomplete laboratory evaluation, and limited treatment options. Standardization and customization of coagulation assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with RBDs. In addition, new therapeutic modalities, both recombinant and plasma derived, are emerging, at least in developed countries. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are appropriately diagnosed and properly treated. Expansion and harmonization of international registries has been initiated to correlate genotype, laboratory, and clinical phenotypes including bleeding severity to improve the diagnosis and therapeutic approach. This review focuses on the latest advances in our understanding, diagnosis, and treatment of RBDs.
Topics: Clinical Laboratory Techniques; Hematologic Tests; Hemorrhagic Disorders; Hemostasis; Humans; Molecular Diagnostic Techniques; Rare Diseases
PubMed: 25712993
DOI: 10.1182/blood-2014-08-532820 -
Clinical Imaging Jul 2021Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a... (Review)
Review
Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects.
Topics: Cerebral Arteries; Diagnostic Imaging; Hemangioma, Cavernous, Central Nervous System; Humans; Skin; Telangiectasia, Hereditary Hemorrhagic
PubMed: 33493737
DOI: 10.1016/j.clinimag.2021.01.020 -
Revista Medica de Chile Mar 2019Acquired hemophilia A (AHA) is a rare and life-threatening autoimmune hemorrhagic disorder where autoantibodies are developed against factor VIII. An early diagnosis is... (Review)
Review
Acquired hemophilia A (AHA) is a rare and life-threatening autoimmune hemorrhagic disorder where autoantibodies are developed against factor VIII. An early diagnosis is challenging and mandatory: an immediate hemostatic control is required to reduce morbidity and mortality. Laboratory features of AHA are: presence of autoantibodies against factor VIII, prolonged activated partial thromboplastin time (with normal prothrombin time and thrombin time) and decreased factor VIII levels. In some cases, the results of laboratory tests may be incorrect due to errors in analysis, blood extraction or manipulation of samples; also worth of consideration are limitations in the measurement range and low sensitivity of the tests. This review highlights the importance of adequate screening in patients with suspected AHA to make an adequate diagnosis and reduce overall fatal outcomes.
Topics: Autoantibodies; Autoimmune Diseases; Blood Coagulation Tests; Early Diagnosis; Factor VIII; Hemophilia A; Humans; Partial Thromboplastin Time
PubMed: 31344171
DOI: 10.4067/S0034-98872019000300334 -
Seminars in Thrombosis and Hemostasis Mar 2021Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to... (Review)
Review
Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.
Topics: Genetic Therapy; Hemorrhagic Disorders; Humans
PubMed: 33636747
DOI: 10.1055/s-0041-1722862