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Bleeding Disorder

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Maha Othman – 1st expert on this subject based on the ideXlab platform

  • platelet type von willebrand disease three decades in the life of a rare Bleeding Disorder
    Blood Reviews, 2011
    Co-Authors: Maha Othman


    Almost thirty years has passed since the description of platelet-type von Willebrand disease. Named initially pseudo-von Willebrand disease, this mild mucocutaneous Bleeding Disorder has an intrinsic defect in platelets rather than VWF. Due to its unique features and its similarity to the more common type 2B VWD, many investigators were intrigued by its nature, pathophysiology and molecular genetics aspects. The challenges to diagnose this Disorder have created debate in literature about the best method of discrimination from type 2B VWD. The recent development of the PT-VWD mouse model carries huge potential for further understanding of the disease as well as the platelet defect and its influence on other biological processes. This review provides a basic as well as updated knowledge about the PT-VWD including history, clinical and laboratory features and treatment in addition to the diagnostic challenges with a focus on molecular genetics aspects and PT-VWD research.

Dianna M Milewicz – 2nd expert on this subject based on the ideXlab platform

  • coagulation factor v a2440g causes east texas Bleeding Disorder via tfpiα
    Journal of Clinical Investigation, 2013
    Co-Authors: Lisa M Vincent, Sinh Tran, Ruzica Livaja, Tracy A Bensend, Dianna M Milewicz, Bjorn Dahlback


    The autosomal dominantly inherited east Texas Bleeding Disorder is linked to an A2440G variant in exon 13 of the F5 gene. Affected individuals have normal levels of coagulation factor V (FV) activity, but demonstrate inhibition of global coagulation tests. We demonstrated that the A2440G mutation causes upregulation of an alternatively spliced F5 transcript that results in an in-frame deletion of 702 amino acids of the large activation fragment, the B domain. The approximately 250-kDa FV isoform (FV-short), which can be fully activated by thrombin, is present in all A2440G carriers’ plasma (n = 16). FV-short inhibits coagulation through an indirect mechanism by forming a complex with tissue factor pathway inhibitor-α (TFPIα), resulting in an approximately 10-fold increase in plasma TFPIα, suggesting that the TFPIα:FV-short complexes are retained in circulation. The TFPIα:FV-short complexes efficiently inhibit thrombin generation of both intrinsic and extrinsic coagulation pathways. These data demonstrate that the east Texas Bleeding Disorder–associated F5 A2440G leads to the formation of the TFPIα:FV-short complex, which inhibits activation and propagation of coagulation.

  • characterization of a novel autosomal dominant Bleeding Disorder in a large kindred from east texas
    Blood, 2001
    Co-Authors: Shao Qing Kuang, Sumera N Hasham, Martin D Phillips, David S Wolf, Perumal Thiagarajan, Dianna M Milewicz


    A large east Texas family with autosomal dominant inheritance of a novel Bleeding Disorder has been identified. The Disorder is characterized clinically by easy bruising, life-threatening Bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors are all within normal limits. To determine the molecular basis of this disease, a candidate gene linkage analysis in this kindred was done. Initially it was hypothesized that the cause of the disease in this family could be an antithrombin III (AT3) mutation that resulted in a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family and an intragenic polymorphic marker within the AT3 gene showed that the disease mapped to this locus. The coding region and intron/exon junctions of AT3 were sequenced using the proband’s DNA, but this analysis failed to identify a mutation. Additional family members were recruited for the study, and 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombinants, the critical interval for the defective gene was narrowed to approximately 1.5 Mb, centromeric to AT3 . The factor V (FV) gene was mapped into the disease interval and sequenced; there were no mutations found. Elucidation of the genetic defect causing the Bleeding Disorder in this family may reveal a novel protein involved in the coagulation cascade.

Shannon Jackson – 3rd expert on this subject based on the ideXlab platform

  • suspected collagen Disorders in the Bleeding Disorder clinic a case control study
    Haemophilia, 2013
    Co-Authors: Shannon Jackson, L Odiaman, R T Card, M C Poon


    Disorders of collagen are associated with a mild Bleeding tendency because of the potential abnormal interaction of collagen, von Willebrand factor (VWF) and platelets required during primary haemostasis and due to generalized soft tissue fragility. Abnormal collagen may contribute to Bleeding in existing mucocutaneous Bleeding Disorders, but the prevalence in this setting is unknown. Generalized symptomatic joint hypermobility (SJH) is common in collagen Disorders and may be objectively measured. To assess the association between symptomatic joint hypermobility and mucocutaneous Bleeding Disorders, we performed a case–control study in which case subjects were 55 consecutive individuals who had visited our Bleeding Disorder clinic with a diagnosis of von Willebrand disease, low von Willebrand factor levels, mild platelet function Disorder or undefined Bleeding Disorder. Controls were 50 subjects without a Bleeding Disorder, and were age and gender matched to the cases. All subjects were assessed with: (i) Beighton score for joint hypermobility, (ii) revised Brighton criteria, (iii) Condensed MCMDM1-VWD Bleeding questionnaire, and (iv) haemostasis laboratory studies. The prevalence of SJH/suspected collagen Disorder in the Bleeding Disorder clinic was 24% (13/55) compared with 2% (1/50) in the control population (OR 15, 95% CI 2–121). Seventy-seven per cent of Bleeding Disorder clinic SJH subjects (10/13) had a prior personal or family history of Ehlers-Danlos, Benign Joint Hypermobility Syndrome or Osteogenesis Imperfecta (OI). Symptomatic joint hypermobility was associated with increased odds of an underlying mucocutaneous Bleeding Disorder. These findings suggest that a collagen Disorder is common and often unrecognized in the Bleeding Disorder clinic as a potential contributor to the Bleeding symptoms.

  • prevalence of suspected collagen Disorders in the adult Bleeding Disorder clinic
    Blood, 2010
    Co-Authors: Shannon Jackson, L Odiaman, R T Card, Morna Brown, Carol Spitzer, Manchiu Poon


    Abstract 1399 Background: Disorders of collagen may be associated with a mild Bleeding tendency because of the interaction of collagen with von Willebrand factor (VWF) and platelets required during primary hemostasis and generalized soft tissue fragility. Therefore, collagen Disorders may be unrecognized contributors to existing Disorders of primary hemostasis. Synergism between these entities could produce a more significant Bleeding tendency than predicted based on laboratory abnormalities alone. Symptomatic joint hypermobility (SJH) is found in over 90% of collagen Disorders and can be objectively measured as a surrogate marker of a potential collagen Disorder. Objective: To determine the prevalence of suspected collagen Disorders in a cohort of adult subjects with mucocutaneous inherited Bleeding Disorders in comparison to healthy controls using SJH as a marker for a potential collagen Disorder. Methods: Fifty-five consecutive subjects, ≥ 16 years of age, attending the Adult Bleeding Disorders (BD) Clinic with a history of von Willebrand disease, platelet function Disorder or undefined Bleeding Disorder and 60 controls (age and sex-matched) were enrolled between June 2008 and February 2010. All subjects were assessed for: i) Generalized joint hypermobility, defined using the Beighton score whereby a score of ≥ 4 out of 9 is considered positive; ii) SJH, defined using the major Brighton criteria which is a Beighton score of ≥ 4 AND arthralgia for longer than 3 months in 4 or more joints; and, iii) Bleeding score (BS), using the Condensed MCMDM1-VWD, with a positive score defined as ≥ 4 for both sexes. CBC, blood group, VWF:Ag, VWF:RCo, FVIII:C and closure times were collected prospectively in the control group and retrospectively in the clinic subjects in addition to Bleeding time and platelet aggregation studies. Results: The prevalence of SJH with a positive Bleeding score was 24% in the BD clinic and 1.6% in controls (see table). Seventy-seven percent of SJH subjects (10/13) in the BD clinic had a prior personal or family history of Ehlers-Danlos Syndrome, other Joint Hypermobility Syndrome or Osteogenesis Imperfecta (OI). Only the OI subject had prior clinical documentation of a collagen Disorder. There was no statistical difference in laboratory measures of hemostasis or Bleeding score in the BD clinic subjects with or without SJH. Of interest, mean Bleeding time in the BD clinic subjects (available in 38 subjects) was 10.5 minutes in the SJH group and 10 minutes in the non-SJH group suggesting that Bleeding time is not a good screening test for the presence of abnormal collagen. Isolated joint hypermobility (Beighton score of ≥ 4) not associated with arthralgia was common in both groups (40% and 30% respectively) in this predominately female population of subjects with inherited mucocutaneous Bleeding. Conclusions: SJH suggesting a collagen Disorder is common and often unrecognized in the BD clinic as a potential contributor to the Bleeding symptoms. Asymptomatic joint hypermobility is common in this predominately female population and not an adequate screening tool for a potential collagen Disorder. A prolonged Bleeding time did not predict the presence of SJH in this cohort. Further study is required to confirm the nature of collagen Disorders in the BD clinic population and the relationship to Bleeding manifestations. Disclosures: No relevant conflicts of interest to declare.