Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemophilia A is an X-linked bleeding disorder caused by a deficiency of factor VIII. As an essential cofactor in the intrinsic clotting cascade, factor VIII is activated and subsequently inactivated by proteolytic cleavages involving factor IIa (thrombin), factor Xa and activated protein C (APC). Investigation of the thrombin cleavage sites at amino acids 372 and 1689 of the factor VIII protein by oligonucleotide screening, DNA amplification and direct sequencing, enabled us to identify two missense mutations in 441 unrelated haemophiliacs. A C-to-T transition, which leads to the substitution of cysteine for arginine at position 1689, was found in a severely affected patient and a previously undescribed G-to-A substitution, causing replacement of arginine1689 with histidine, was found in a patient with mild disease.
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PMID:Detection and characterisation of two missense mutations at a cleavage site in the factor VIII light chain. 185 41

Hemophilia B is an X-linked bleeding disorder. We report on female twins, who were conspicious in prolonged bleeding after venipuncture as well as hematomas after intramuscular injections even in the first months of their life. Their father suffering from a severe hemophilia B deceased in 1992. Their mother, half-brother and grandmother from their father's side had no signs of bleeding disorders. Clotting analysis performed in both twins revealed a markedly prolonged partial thromboplastin time (> 100 s). The factor IX levels were below 2%. In order to detect mutations, a general screen using the polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) analysis of the PCR products have been performed. PCR products have been cut into smaller fragments using restriction endonucleases (RE) for an in-depth SSCP screen. A general screen for gross abnormalities in the factor IX gene including deletions, insertions and rearrangements was performed by Southern blot analysis of RE-digests of genomic DNA using the factor IX cDNA as a hybridization probe. Furthermore, we screened for mutations in the CG dinucleotides comprising part of RE-recognition sequences (exon 1, 2, 3, 4, 5, and 8). By all methods applied herein, no mutations have been detected in these twins. On the basis of our results the hemophilia B of these twins might be explained by extreme non-random lyonization.
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PMID:Female twins with severe Christmas disease (hemophilia B). 790 44

Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.
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PMID:Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. 988 31

Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (FIX). Using adeno-associated virus (AAV)-mediated, liver-directed gene therapy, we achieved long-term (> 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an FIX null mutation. This was accomplished with a comparatively low dose of 1 x 10(12) vector genomes/kg. Canine FIX (cFIX) levels rose to 5% to 12% of normal, high enough to result in nearly complete phenotypic correction of the disease. Activated clotting times and whole blood clotting times were normalized, activated partial thromboplastin times were substantially reduced, and anti-cFIX was not detected. The fourth animal, also a null mutation dog, showed transient expression (4 weeks), but subsequently developed neutralizing anti-cFIX (inhibitor). Previous work in the canine null mutation model has invariably resulted in inhibitor formation following treatment by either gene or protein replacement therapies. This study demonstrates that hepatic AAV gene transfer can result in sustained therapeutic expression in a large animal model characterized by increased risk of a neutralizing anti-FIX response.
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PMID:Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. 1267 97

Hemophilia B is a hereditary bleeding disorder from the deficiency of factor IX (FIX) activity. Hemophilia B is caused by a mutation in the F9 gene on Xq27.1 encoding FIX and, thus, has an X-linked inheritance. The diagnosis of hemophilia B is typically suspected by significantly prolonged activated partial thromboplastin time (aPTT) on screening tests, but aPTT may be normal or minimally prolonged in mild hemophilia B. We herein describe the cases of two Korean brothers with mild hemophilia B. The proband was a 26-year-old male patient with a mild bleeding history. He had a younger brother and a male cousin of maternal side with a similar bleeding tendency. Coagulation screening tests revealed no remarkable findings, including normal aPTT at 40.0 s (STA-PTT Automate, local reference range, 29.1-41.9 s). However, factor assays revealed a significantly decreased FIX activity at 27% (67-154%). The younger brother also had mildly prolonged aPTT at 45.1 s, which was corrected on mixing test. His FIX activity was 34%. Molecular genetic analysis of F9 revealed that the brothers were both hemizygous for a missense mutation, c.280G>A (p.Gly94Arg or Gly48Arg by conventional numbering based on the mature protein). Gly94Arg (Gly48Arg) is a mutation previously described in mild hemophilia B. This report shows that aPTT can be normal even with a reagent reported to be sensitive in detecting mild hemophilia B. It is important to pay attention to the clinical and family history and perform factor assays, and molecular genetic analysis can confirm the diagnosis and reveal genotype-phenotype correlations.
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PMID:A diagnostic challenge: mild hemophilia B with normal activated partial thromboplastin time. 2030 39

Haemophilia A (HA) and B (HB) are X-linked congenital disorders caused by deficiencies of Factor VIII and FIX. Being the world's most populous country, China potentially has a large population of haemophilia patients. During the last decade, no studies have been published regarding the clinical information of haemophilia in China. A retrospective study was conducted in patients with HA and HB referred to Tianjin Haemophilia Centre between 2002 and 2012. We identified 1,226 males with haemophilia (1,019 HA and 207 HB). The results revealed that activate partial thromboplastin time was negatively correlated plasma factor level of person with haemophilia. Our data did not offer sufficient evidence of any relationship existed between disease severity and risk or site of haemorrhage. There was a trend toward a higher inhibitor incidence induced by plasma-derived factor VIII products, than by recombinant FVIII (rFVIII) alone. It seemed that second generation of rFVIII more likely developed inhibitor, and first generation of rFVIII was nevertheless more closely connected to high-titer inhibitor. We found that delay in diagnosis and blood-borne infections were significantly reduced, while the joint deformity rate did not decrease despite the wide variety of products to choose from in this decade. The development of inhibitor still remains a major challenge in replacement therapy in haemophilia.
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PMID:Retrospective analysis of 1,226 Chinese patients with haemophilia in a single medical centre. 2419 52

Hemophilia A (HA) is an X-linked hereditary bleeding disorder caused by deficiency of coagulation factor (F) VIII activity. One of the greatest complications in the treatment of HA is the development of neutralizing alloantibodies, known as FVIII inhibitors. HA patients who develop FVIII inhibitors have limited treatment options available to them and experience greater disease- and treatment-related burdens than HA patients without FVIII inhibitors. Emicizumab, a recently approved bispecific monoclonal antibody, mimics the function of FVIIIa by bridging FIXa and FX to restore effective hemostasis. Although emicizumab and FVIII show some functional similarities, several key differences influence the results of standard laboratory assays when conducted in the presence of emicizumab, and can result in a misleading interpretation of coagulation assays in emicizumab-treated patients. Here, we discuss current laboratory monitoring methods, including activated partial thromboplastin time, FVIII one-stage clotting assays, FVIII chromogenic assays, and global coagulations assays; address why these conventional methods may be inappropriate for monitoring of HA patients receiving emicizumab; and suggest alternative methods applicable to monitoring HA treatment in an evolving treatment landscape.
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PMID:Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A. 3120 78

Objective: Patients with hereditary bleeding disorders rarely present with intraocular or orbital hemorrhage as the initial symptom. The presence of such a condition can be easily overlooked when contemplating ophthalmic surgery, and can give rise to intraoperative and postoperative complications. Awareness of such conditions can improve surgical decisions. Methods: This is a case report of an eight-year-old Filipino male who sustained blunt trauma to his right eye, causing traumatic total hyphema with corneal staining. Subretinal hemorrhage was seen on ultrasound. The patient underwent anterior chamber washout with temporary keratoprosthesis and pars plana vitrectomy with silicone oil tamponade. Clearance of the hyphema was noted postoperatively. However, on follow-up after 19 days, the patient presented with recurrence of hyphema, new onset proptosis and peribulbar hemorrhage. Results: Imaging of the orbit revealed new-onset pseudoproptosis with intraocular and peribulbar hemorrhage. A bleeding disorder was suspected at this point. Further probing revealed a family history of prolonged bleeding time in an X-linked genetic inheritance pattern spanning three generations. Laboratory testing of prothrombin, partial thromboplastin, and factor assays were done, which revealed factor VIII deficiency, diagnostic of hemophilia A. No further surgery was done. The patient was given transfusions of fresh frozen plasma, which resolved the hemorrhage. Conclusions: Bleeding disorders present a dilemma in the surgical management of patients. In cases of traumatic hemorrhage, adequate history and physical examination should always be done to rule these out. Surgical outcomes in hemophiliacs can be improved with preoperative prophylactic treatment and close postoperative monitoring and care.
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PMID:Hemophilia presenting as recurrent ocular hemorrhage. 3226 13

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