Bleeding Disorders In Patients Research Articles

Advances in the treatment of inherited coagulation disorders

Inherited coagulation disorders constitute a broad spectrum of coagulation factor deficiencies that include X-linked factor (F)VIII or FIX deficiency that causes haemophilia, and autosomal recessive disorders producing heterogeneous deficiencies in fibrinogen (FI), prothrombin (FII), FV, FVII, FX, FXI, FXIII and combined FV+FVIII. Significant advances in treatments for patients with congenital haemophilia A (FVIII deficiency) and B (FIX deficiency) over the last two decades have resulted from improvements in the production, availability and patient access to factor replacement products. Translation of advances in biotechnology, namely recombinant protein technology, targeted protein modifications to improve function and potentially reduce immunogenicity, and advanced formulations to optimize bioavailability and sustain activity offer promisingly new treatments for haemophilia as well as recessively inherited bleeding disorders in patients who otherwise have few therapeutic options. Though a theoretical risk remains for blood-borne viral infections with pooled plasma-derived products, this concern has diminished with breakthroughs in purification and viral inactivation methods. Development of inhibitory antibodies is still the most daunting problem for patients with inherited bleeding disorders, complicating treatment approaches to control and prevent bleeding, and posing risks for allergic and anaphylactic reactions in susceptible patients. The objectives of this review are to (i) highlight emerging advances in hemostatic therapies that are bioengineered to improve pharmacokinetic properties and bioavailability, sustain functional activity, and possibly eliminate immunogenicity of recombinant factor proteins; and (ii) present an overview of key clinical trials of novel factor products currently in the development pipeline.

P-001 Structural investigation of protein Z mutations within the exon 8 in patients with fetal losses

s / Thrombosis Research 131, Suppl. 1 (2013) S71–S103 S77 is a loop region which is in contact with the longest helix of PZI. Other regions have been identified, which hold anomalous flexibility associated with potentially protective gene variants. A possible explanation of the effect of the observed gene variants is given, based on the interaction between PZ and PZI. P-002 Underlying bleeding disorders in patients are equally important in menorrhagia with and without gynaecological abnormalities H.M. Knol 1,2, A.B. Mulder 3, D.H. Bogchelman2, H.C. Kluin-Nelemans1, A.G.J. van der Zee2, K. Meijer 1 1Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen; 2Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen; 3Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the

P-002 Underlying bleeding disorders in patients are equally important in menorrhagia with and without gynaecological abnormalities

P-002 Underlying bleeding disorders in patients are equally important in menorrhagia with and without gynaecological abnormalities

Clinical Progress in Gene Therapy: Sustained Partial Correction of the Bleeding Disorder in Patients Suffering from Severe Hemophilia B

Human Gene TherapyVol. 23, No. 1 CommentariesClinical Progress in Gene Therapy: Sustained Partial Correction of the Bleeding Disorder in Patients Suffering from Severe Hemophilia BT. VandenDriessche and M.K. ChuahT. VandenDriesscheDepartment of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), B-1090 Brussels, Belgium.Center for Molecular and Vascular Biology, University of Leuven, B-3000 Leuven, Belgium.Search for more papers by this author and M.K. ChuahDepartment of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), B-1090 Brussels, Belgium.Search for more papers by this authorPublished Online:16 Jan 2012https://doi.org/10.1089/hum.2011.221AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited ByHaemophilia gene therapy: From trailblazer to gamechanger21 May 2018 | Haemophilia, Vol. 24, No. S6Hemophilia Gene Therapy: Ready for Prime Time? Thierry VandenDriessche and Marinee K. Chuah1 November 2017 | Human Gene Therapy, Vol. 28, No. 11Gene Therapy: Charting a Future Course—Summary of a National Institutes of Health Workshop, April 12, 2013 Marina O'Reilly, Howard J. Federoff, Yuman Fong, Donald B. Kohn, Amy P. Patterson, Nabil Ahmed, Aravind Asokan, Shannon E. Boye, Ronald G. Crystal, Satiro De Oliveira, Linda Gargiulo, Scott Q. Harper, Yasuhiro Ikeda, Robert Jambou, Maureen Montgomery, Lawrence Prograis, Eugene Rosenthal, Daniel H. Sterman, Luk H. Vandenberghe, Laurie Zoloth, Mehrdad Abedi, Jennifer Adair, Prasad S. Adusumilli, William F. Goins, Jhanelle Gray, Paul Monahan, Leslie Popplewell, Miguel Sena-Esteves, Bakhos Tannous, Thomas Weber, William Wierda, Rashmi Gopal-Srivastava, Cheryl L. McDonald, Daniel Rosenblum, and Jacqueline Corrigan-Curay28 April 2014 | Human Gene Therapy, Vol. 25, No. 6Inhibitors - cellular aspects and novel approaches for tolerance25 April 2014 | Haemophilia, Vol. 20Gene therapy for hemophilia30 June 2013 | Journal of Thrombosis and Haemostasis, Vol. 11Hemophilia clinical gene therapy: brief reviewTranslational Research, Vol. 161, No. 4Current World LiteratureCurrent Opinion in Pediatrics, Vol. 24, No. 6Platelet-directed gene therapy overcomes inhibitory antibodies to factor VIII14 August 2012 | Journal of Thrombosis and Haemostasis, Vol. 10, No. 8Recent Progress in Gene Therapy for Hemophilia Marinee K. Chuah, Nisha Nair, and Thierry VandenDriessche6 June 2012 | Human Gene Therapy, Vol. 23, No. 6Advanced therapies for hemophilia: reality or fantasy?10 January 2014 | Expert Review of Hematology, Vol. 5, No. 3 Volume 23Issue 1Jan 2012 InformationCopyright 2012, Mary Ann Liebert, Inc.To cite this article:T. VandenDriessche and M.K. Chuah.Clinical Progress in Gene Therapy: Sustained Partial Correction of the Bleeding Disorder in Patients Suffering from Severe Hemophilia B.Human Gene Therapy.Jan 2012.4-6.http://doi.org/10.1089/hum.2011.221Published in Volume: 23 Issue 1: January 16, 2012Online Ahead of Editing: December 12, 2011PDF download

Correlation of a Condensed Bleeding Score with New Diagnosis of a Congenital Bleeding Disorder in Patients Referred to a Tertiary Centre

Abstract 1226▪▪This icon denotes a clinically relevant abstractThe performance and utility of a condensed bleeding score (Bowman et al, J Thromb Haemost., 2008;6:2062) in relation to the diagnosis of a congenital bleeding disorder in new referrals to a regional haemostasis clinic over an 8 month period is presented. Between November 2010 and June 2011, 50 patients over the age of 16 (median age, 31 years; range, 16–79), including 32 females, were referred for investigation of a possible congenital bleeding disorder following detection of abnormal coagulation results and/or presentation with a bleeding history. A bleeding score was performed as part of their initial assessment. 12(24%) patients were from local referral and 38(76%) patients were referred from other hospitals in the region for further investigation of a suspected bleeding disorder. Basic coagulation tests (activated partial thromboplastin time (APTT), prothrombin time Clauss fibrinogen and platelet count) were normal in the referred patients from other centres. 50% (6/12) of the local referrals were for investigation of a prolonged APTT detected on routine coagulation screening prior to major surgery.The median bleeding score was 6 with a range of −1 to 14 (Table 1). The presence of a congenital bleeding disorder was confirmed in 31 of the 50 patients (62%), including 19/31 (61%) of the female patients and 12/31(39%) of the males. Correlation of an abnormal bleeding score (score ≥ 4) with diagnosis of a congenital bleeding disorder was only seen for diagnosis of type 1 Von Willebrand Disease (VWD) (Table 2). Analysis of the cases with low scores and abnormal results identified two groups of patients; firstly, those who had not yet had a significant haemostatic challenge, and secondly, those in whom the abnormal coagulation results were explained by a non-haemostatically significant reduction in a coagulation factor level (e.g. FVII, 15%; dysfibrinogenaemia; F XII deficiency). These clinically insignificant laboratory abnormalities explain the discrepancy between the number of patients with abnormal laboratory tests (35) and the number of patients diagnosed with a congenital bleeding disorder (31).Table 1Bleeding score (range)Number of patients with normal lab resultsNumber of patients with abnormal lab results−1 to +1382–44105–74128–102311–1422Total1535Table 2DiagnosisNumber of patientsMedian bleeding scoreAge rangeType 1 VWD116 (4–10)17–51Type 2 VWD48 (5–13)17–36Factor XI123 (1–8)17–76Platelet function defect46 (2–9)17–57Compared to previous reports the range of scores found with this assessment tool was narrow and could not exclude patients from further laboratory assessment. However the condensed bleeding score has only been validated prospectively for the diagnosis of type 1 VWD and all patients in this cohort who were diagnosed with type 1 VWD had an abnormal bleeding score (≥ 4). This observation supports the role of this scoring system in the assessment of patients for type 1 VWD. The use of the condensed bleeding score in assessing patients with suspected factor XI deficiency is difficult due to the lack of a phenotypic relationship between residual factor XI activity and a bleeding tendency. Furthermore, although factor XI deficiency is a rare congenital bleeding disorder in our cohort of patients 12/31(39%) were diagnosed with factor XI deficiency. This may explain the overall lack of correlation between bleeding score and diagnosis of a congenital bleeding disorder. Patients who have an abnormal bleeding score but normal laboratory tests need consideration of further investigations before concluding they are normal. The possibility of an acquired bleeding disorder should be considered. A thorough drug history is also important as one of the patients with a bleeding score of 14 was taking a non-steroidal anti-inflammatory drug.The use of the condensed bleeding score in the detection of congenital bleeding disorders other than type 1 VWD requires further validation in a larger number of patients. Disclosures:No relevant conflicts of interest to declare.

Stellenwert von Gerinnungsstörungen bei Patienten mit Epistaxis

Epistaxis can have a variety of different local or systemic causes. It is the cardinal symptom of von Willebrand disease (VWD), the most frequent congenital bleeding disorder with a prevalence of approximately 1%. The usual routine coagulation screening tests (PT, APTT, platelet count) are not sufficient to diagnose VWD, factor XIII (FXIII)-deficiency or platelet dysfunction. A prospective study was conducted implementing enhanced coagulation screening for bleeding disorders in a total of 100 inpatients admitted for epistaxis. A bleeding disorder was found in 13%. In eight patients VWD was diagnosed, in six patients FXIII-deficiency was found, and in one patient both. The prevalence of bleeding disorders in patients with epistaxis is higher than in the general population. Epistaxis can be the primary symptom of chronic inflammatory disease or malignant disease. A thorough anamnesis is necessary and in cases of doubt additional testing for underlying disorders is recommended.

Template bleeding time for preoperative screening in patients having orthognathic surgery

Excessive blood loss is a serious but rare complication of orthognathic surgery. The aim of this study was to find out whether template bleeding time (TBT) could detect primary bleeding disorders in patients having orthognathic operations and how many false positive tests there were. We also examined the correlation between the perioperative bleeding rate and the result of preoperative TBT. Patients who had orthognathic operations at Karolinska University Hospital, Huddinge, from August 2001 to December 2006, were screened preoperatively by measuring TBT and the records of their operations were reviewed retrospectively. Prolonged TBT was recorded in 20 patients (13%), 19 female and 1 male ( P = 0.02). After further examination, 10 of these patients were found to have a primary disorder of haemostasis. No detectable reason for the prolonged TBT could be found in the others. There was no significant difference in perioperative bleeding rate between patients with prolonged and normal TBT or between TBT and perioperative bleeding rate. In conclusion , the routine use of preoperative TBT for haemostatic screening in orthognathic surgery cannot be recommended because of the large number of false positive results. There was no significant correlation between prolonged TBT and bleeding during orthognathic surgery.

Thromboelastographic Tracings in Retired Racing Greyhounds and in Non‐Greyhound Dogs

Bleeding disorders in patients with normal coagulation test results are frequently reported in Greyhounds. The purpose of this study was to compare Greyhounds to non-Greyhounds by thromboelastography (TEG). TEG parameters in Greyhounds are different from those in non-Greyhounds. Forty-three healthy dogs (28 Greyhounds and 15 non-Greyhounds) based on the results of physical examination, CBC, activated partial thromboplastin time, prothrombin time, fibrinogen, and platelet count. Recalcified citrated native TEGs were performed in both groups; data were compared using Student's, Mann-Whitney, and Pearson's statistical tests. In Greyhounds, mean +/- SD were as follows: R-time 4.3 +/- 1.7 minutes, K-time 3.8 +/- 1.4 minutes, angle (alpha) 50.0 +/- 8.0 degrees , maximum amplitude (MA) 47.6 +/- 5.6 mm, clot strength (G) 4,647 +/- 1,097 dyn/cm2, and percent lysis at 60 minutes (LY60) 2.8 +/- 5.0%. In the non-Greyhounds they were R-time 3.7 +/- 1.6 minutes, K-time 2.5 +/- 0.9 minutes, angle 59.8 +/- 7.0 degrees , MA 53.1 +/- 5.6 mm, G 5,811 +/- 1,256 dyn/cm2, and LY60 3.1 +/- 2.5%. All parameters were significantly different between the groups, except for R-time and LY60. In Greyhounds, clotting kinetics are slower and clot strength are weaker than in non-Greyhounds, supporting the increased tendency to bleed observed after minor trauma or surgical procedures in the breed. The findings may also be attributed to blood viscosity or to the concentration of citrate in the sample (ie, Greyhounds have higher hematocrit and less plasma per unit volume).

A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice

Pentosan polysulfate (PPS) is a heparin-like polysaccharide that can affect the binding interactions of fibroblast growth factor (FGF-2) with its high-affinity receptors. Patients with angiogenic tumors frequently show high levels of FGF-2 in the circulation. Since FGF-2 is a heparin-binding angiogenic growth factor, PPS has been used successfully to block its activity in patients with angiogenic tumors. However, because of its heparin-like activity, the major toxic effect of PPS is the development of bleeding disorders. The role that circulating FGF-2 plays in the pathogenesis of bleeding disorders in patients treated with PPS is currently unknown. Here we hypothesized that FGF-2 might play a physiological role in the pathogenesis of intestinal bleeding induced by PPS. This hypothesis is supported by previous studies showing that PPS is accumulated in the intestine and that circulating FGF-2 specifically binds to and modulates the angiogenic activity of intestinal submucosal endothelial cells. We used recombinant adenoviral vectors carrying a secreted form of FGF-2 and LacZ control vectors to determine whether high levels of circulating FGF-2 facilitate the development of intestinal bleeding disorders in FVB/N and C57BL/6J mice treated with PPS. We found that PPS, acting together with FGF-2, induced structural changes in intestinal vessels leading to the development of lethal intestinal hemorrhages. These findings might have wider clinical implications for the systemic use of PPS and other heparinoids in the treatment of patients with angiogenic diseases associated with high levels of circulating FGF-2.

Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6‐year survival in patients with chronic liver disease

Alterations of plasma coagulation factor XIII may contribute to bleeding disorders in patients with liver cirrhosis. As standard clotting tests such as prothrombin time or activated thromboplastin time (aPTT) cannot detect factor XIII deficiency, this may often be overlooked in clinical practice. We aimed to define factor XIII's clinical and prognostic role in chronic liver disease. Factor XIII activities were assessed among various other parameters in 111 patients with chronic liver diseases during evaluation for liver transplantation in a prospective study. Unlike coagulation factors II, V or VII, factor XIII activity was maintained in the majority of patients with liver cirrhosis. However, although rarely, factor XIII deficiencies (<50%) occurred, especially in Child C cirrhosis. Factor XIII levels correlated with liver's biosynthetic capacity (cholinesterase activity, albumin, total protein) as well as with platelet count, global coagulation tests and other single coagulation factors. Patients reporting a current systemic bleeding tendency at study entry had significantly reduced factor XIII. In a 6-year follow-up, patients with factor XIII<50% had a significantly increased risk of severe upper gastrointestinal bleed, and reduced factor XIII (<50%, 50-75% vs. normal) was associated with increased mortality. Factor XIII deficiency is rare in patients with liver cirrhosis, but is associated with a clinical bleeding tendency and an unfavorable prognosis for future hemorrhages and survival.

Idiopathic thrombocytopenic purpura in childhood: Controversies and solutions

Idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder in patients who are otherwise healthy and present with thrombocytopenia with normal red cells and leukocytes. ITP is a diagnosis of exclusion and is in origin heterogeneous. The unknown etiology and the lack of clinical data from controlled prospective studies are reasons for controversies in diagnosis and management. Study endpoints traditionally include the velocity of platelet increase after drug intervention or observation, although a rapid elevation of the platelet count is of questionable clinical value. Evaluation of other endpoints is needed.

The spectrum of bleeding disorders in women with menorrhagia: a report from Western India.

In order to evaluate the incidence of hereditary bleeding disorders in patients presenting with menorrhagia, where the usual gynecological and endocrinal causes of bleeding were ruled out by various local ultrasonography (USG) and relevant endocrine investigations, 120 women aged between 18 and 35 years presenting with menorrhagia without any discernable cause were studied using an open design, where the investigators knew that these patients had menorrhagia. These patients were investigated for inherited coagulation defects. Of the 120 women investigated, 19.16% (23 cases) had an inherited coagulation disorder to account for their menorrhagia. Although a majority (11.6%) are patients with von Willebrand's disease (VWD), other rare platelet disorders such as Glanzmann's thrombasthenia (3.3%), Bernard-Soulier syndrome (0.83%), coagulation factor deficiencies such as factor VIII (0.83%), factor X (0.83%), and factor XI (0.83%), and immune thrombocytopenia (0.83%) were also found. Taking a detailed history for bleeding from other sites however minor, paternal consanguinity as well as family history of bleeding tendencies appeared as a very strong predictor for such kinds of disease in patients with menorrhagia. Patients with menorrhagia without a discernable cause, therefore, need evaluation for the congenital coagulation disorders.

An assessment of preoperative coagulation screening for tonsillectomy and adenoidectomy

Preoperative coagulation studies are commonly employed in order to try to identify the 2–4% of all patients undergoing tonsillectomy/adenoidectomy surgery who experience hemorrhagic complications. In an atmosphere of increasing cost consciousness, evaluation of the efficacy of screening tests is warranted. The records of 994 out of 1050 patients consecutively scheduled for tonsillectomy, adenoidectomy or T&A over a 2.5-year period were retrospectively reviewed in order to determine the usefulness of partial thromboplastin (PTT) and prothrombin time (PT) screening in predicting surgical and postsurgical bleeding. For patients with no history or clinical signs indicating possible bleeding disorder, preoperative PT and PTT failed to predict bleeding as an outcome. Also no patients were identified in this series to have previously undiagnosed coagulopathies on the basis of screening PT/PTT. The purpose of any screening test is to identify disease early enough for therapeutic intervention to be effective. Although preoperative PT/PTT will occasionally identify an unsuspected von Willebrand's or other coagulopathy, the prevalence of bleeding disorders in patients with negative history and examination is low enough that PT/PTT has essentially a zero predictive value for surgical bleeding. Screening PT/PTT should therefore be reserved for patients with known or suspected coagulopathies.

Complications of Hemophilic Disorders Affecting the Renal Tract

Patients with bleeding disorders may bleed into tissues or from damaged skin and mucosal surfaces. Repeated hemorrhage into joints leads to arthropathy. Bleeding from the renal tract may not be recognized as a sign of a severe bleeding disorder in patients who have not undergone excretory urography. Awareness of other possible causes of hematuria, the possible consequences of retained blood clots, and the risk of progressive renal damage should prompt more frequent investigation of the urinary tract in such patients.