Common Bleeding Disorder Research Articles

A novel VWF variant associated with type 2 von Willebrand disease in German Wirehaired Pointers and German Shorthaired Pointers.

Von Willebrand disease (VWD), caused by deficiency of the von Willebrand factor (VWF), is the most common bleeding disorder in humans and dogs. The complete cDNA encoding VWF of a German Wirehaired Pointer with type 2 VWD was sequenced, and we found four variants that alter the amino acid sequence. These variants were: c.1657T>G corresponding to p.Trp553Gly; c.1777G>A (p.Glu593Lys); c.4937A>G (p.Asn1646Ser) and c.5544G>A (p.Met1848Ile). A haplotype of the c.1657G, c.1777A and c.4937G alleles co-segregated with the VWF antigen level in a four-generation pedigree with the disease. Healthy dogs of the breed were found that were homozygous for the c.1777A or the c.5544A allele, indicating that these variants do not cause VWD. Dogs that were homozygous for the c.4937G allele and had no signs of a bleeding disorder were observed in the Chinese Crested dog breed. Thus, only the c.1657G variant was found in the homozygous state exclusively in VWD affecteds, and this variant is the strongest candidate to be the cause of VWD type 2 in the German Wirehaired Pointer breed. A screen of German Shorthaired Pointers indicated that the variant also segregates with VWD in this breed.

Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis

Haemophilia A (HA) is a common X-linked recessive bleeding disorder and almost one half of patients with severe HA are caused by intron 22 inversion (Inv22) in the F8. Inv22 is considered to be almost exclusively of meiotic origin in germ cells during spermatogenesis and only one mosaic Inv22 female carrier with the mutation possibly occurring during mitosis of the embryo has been reported so far. Previously we have identified a novel complex recombination mediated by int22h copies in a sporadic severe HA pedigree and herein we have localised the sequences flanking the breakpoint region using genome walking technique, AccuCopy technique, gene chip and real-time PCR. The disease causing genetic variant registered an 18.1 kb deletion including part of int22h-1 through the intron 23 of F8 and a 113.3 kb duplication of part of int22h-2 through the intron 1 of TMLHE inserted in the religated region of the F8. Two intrinsically linked mechanisms of recombination-dependent DNA replication: microhomology-mediated break-induced replication (MMBIR) followed by break-induced replication (BIR) might be responsible for the incident of the complex recombination during early embryogenesis of the proband's mother.

Diagnosis or Exclusion of von Willebrand Disease Using Laboratory Testing.

von Willebrand disease (VWD) is a common bleeding disorder diagnosed based on clinical features and following laboratory testing. VWD is due to deficiencies or defects in the plasma protein von Willebrand factor (VWF), a large adhesive protein with multiple activities. Laboratory testing therefore centers on assessment of VWF protein level using VWF antigen (VWF:Ag), as well as assays that measure VWF activity, most notably platelet glycoprotein (GP) Ib and collagen binding (VWF:CB) activities. Decreases in VWF:Ag and VWF activities, as well as the pattern of such changes, help define VWD and its type. Classically, the most often used assay for measuring GPIb binding activity was the ristocetin cofactor assay (VWF:RCo), which historically measured agglutination of fixed human platelets by VWF in the presence of ristocetin. This assay is now often replaced or supplemented with other assays based on binding of VWF to recombinant GPIb, generally without the use of platelets, and with or without ristocetin. This chapter briefly reviews laboratory tests for VWD, as well as recommended approaches to use of such assays to help diagnose or exclude VWD in patients showing clinical features.

Utility of Thromboelastography for the Diagnosis of Von Willebrand Disease

Background: Von Willebrand Disease (VWD) is the most common bleeding disorder. Current gold standard diagnostic testing includes: VWF Activity (VWF:RCo), VWF Antigen (VWF:Ag) and Factor VIII Activity (FVIII). There are many difficulties associated with the current diagnostic methods. Thromboelastography (TEG) is a viscoelastic method of measuring coagulation function. The standard TEG assay has not been thought to be of use in VWD because of the lack of shear stress which is essential for the activation of VWF. Modified TEG using Ristocetin activation has been found to be useful in the diagnosis of VWD. The aims of this study were to evaluate the different parameters of Tissue factor (TF) initiated TEG in patients with VWD, to determine if this assay is sensitive to dysfunctional/low levels of VWF, as this does not require any significant change in procedure except for the use of TF as the activator instead of Kaolin.Methods: A retrospective chart review of patients who presented for a bleeding disorder workup that had TF initiated TEG analysis and Von Willebrand laboratory tests completed between January 2007 and December 2015 was performed. IRB approval was obtained, and current diagnostic tests for Von Willebrand Disease (CBC with platelet count, VWF:RCo and VWF:Ag, FVIII, ABO blood type; PT, PTT, Fibrinogen) and TF initiated TEG parameters, specifically K-Time and MRTG (Maximum rate of thrombin generation), were compared. To perform the TEG analysis, the citrated whole blood samples were activated using 20mL of 1:10,000 dilution of recombinant human tissue factor (Innovin, Dade Behring) and CaCl2.Results: A total sample size of 160 patients (ages ranging 2 weeks to 18 years) who had a workup for a bleeding disorder that included Von Willebrand studies and TEG were reviewed. Of these 160 patients, 75 patients had a VWF:RCo <50 IU/dL. These patients were categorized into two categories for the purposes of this study: Low VWF:RCo (30-50 IU/dL) and Abnormal VWF:RCo (<30 IU/dL). The clinical and lab characteristics of patients studied are presented in Table 1, including FVIII, platelet count, and fibrinogen levels. Fibrinogen levels on 15 patients with VWF:RCo <50 IU/dL were not reported, and are not included in the means as noted in Table 1. The TEG parameter, K-Time, (time for increase in amplitude from 2mm to 20mm representing the dynamics of clot formation, normal <2min) was determined abnormal for values greater than 2.2 (>10% above the normal). Of the patients with VWF:RCo <30 IU/dL, 23/30 (77%) had an abnormal K-Time of >2.2, with a p-value of ≤0.001 (Table 2); whereas patients with low VWF:RCo 30-50 IU/dL, only 13/45 (29%) had an abnormal K-Time of >2.2, which was not statistically significant. A ROC curve for patients with VWF:RCo <30 IU/dL and abnormal K-Time showed an area under the curve of 0.675, with a p-value of 0.003 (Fig 1). An analysis of the MRTG showed a mean of 9.45 in patients with VWF:RCo <30 IU/dL and a mean of 11.26 in patients with normal VWF:RCo, which was statistically significant (p=0.05). There was a moderate correlation (0.33) seen between patients with abnormal K-Time and FVIII, however, when analyzing regression data the correlation only accounts for 11% of the explained variance in abnormal K-Time values. Patients with abnormal K-Time and abnormal fibrinogen levels and platelet counts were also compared, and showed no significant correlation, indicating that these were not the determinants that influenced the K time.Conclusions: The TF activated TEG reflects impaired clot formation in patients with VWF <30% as reflected by the prolongation in the K-Time and the low MRTG. The TEG unlike VWF:RCo can be done in real time and results are available to the clinician within an hour. This will definitely be beneficial in acute situations like evaluation of and management of acute bleeding in patients with acquired deficiencies of VWF and may play an important role in the surgical management of patients with VWD. It will also help physicians monitor response to treatment, frequency of treatment, and the need for prophylactic dosing in patients with VWD. The next step will be to evaluate if this difference is also seen with Kaolin, which is the standard TEG assay. We anticipate that Kaolin being a stronger agonist may make the test less sensitive to VWF related changes. [Display omitted] DisclosuresChitlur:Novo Nordisk: Consultancy; Bayer Pharmaceuticals: Honoraria; Baxalta: Honoraria; Biogen Idec: Honoraria; Pfizer: Honoraria.

Attitudes Toward Prenatal Diagnosis and Pregnancy Management in Carriers of Hemophilia: A Qualitative Analysis Exploring the Views of Carriers in Southern Alberta

Introduction Hemophilia A and B are the most common severe bleeding disorders. Improvements in carrier detection and prenatal diagnosis of hemophilia have practical implications for family planning as well as peri- and antenatal pregnancy management. Access to counselling and testing is heterogeneous. We evaluated the awareness and usage of prenatal genetic counselling, sex determination and procedures to determine fetal hemophilia status over time in carriers of hemophilia at our hemophilia treatment centre (HTC). Methods Carriers of hemophilia A or B were recruited through our HTC. Research was approved by our institutional ethics board approval. An online link was emailed to participants using Research Electronic Data Capture (REDCap) Clinical Research Unit software. Survey questions explored demographics, family members affected and severity, pregnancy history, awareness and utilization of carrier testing, genetic counselling, prenatal diagnostic technologies and terminations. Responses were analyzed by 2 reviewers for basic statistics and to identify themes in a descriptive qualitative design. Results &amp; Discussion 85 hemophilia carriers were identified; 3 were lost to follow up and 34 had missing or incorrect contact information. 48 survey invitations were distributed with 24 responses received (50% response rate). One response was excluded as the participant was not a carrier (spontaneous mutation in her son). 20 complete and 3 incomplete responses were analyzed. Median age was 44 years (28-73), with sons most commonly affected family member (14/23, 61%). 3 participants reported no pregnancies, 2 did not respond and 1 did not list the years of her pregnancies. The majority received genetic counselling from HTC personnel. Table 1. Awareness and utilization of carrier testing, counselling, pregnancy, prenatal technologies and termination. * Denominator represents number of responses **Chorionic villae and/or amniotic fluid testing Responses were analyzed by year of pregnancy: prior to 2000 (n=8) or after 2000 (n=9). No pregnancy dates were given in 6 responses. 100% of participants with pregnancy after 2000 had carrier testing. The majority also received genetic counselling (n=8). Members of this group had access to and utilized prenatal diagnostic technologies; pre-implantation genetic diagnosis (n=1), early prenatal diagnosis (n=2) or invasive testing (n=4). Rationale given included: more time to prepare emotionally (n=3), optimize delivery management (n=2), and as a consideration to terminate pregnancy (n=1). Overall, there was increased but heterogeneous knowledge of available technologies potentially reflecting limited understanding during or ineffectively timed counselling, or limited knowledge by carriers who had completed their families when these technologies became available. Identified categories and themes from text responses include: · Impact of family experience with hemophilia: o Themes: severely affected family members impact family planning and attitudes about hemophilia, prenatal diagnosis does not prompt termination due to improvements in hemophilia care · Impact on medical care: o Themes: early identification may prepare for delivery, concern about overtreatment of carriers during delivery · Impact on psychosocial well-being: o Themes: concern about others' opinions, guilt for having more than one affected child · Need for education: o Themes: importance of collaboration between HTC and health care providers, HTC as the primary source for hemophilia related information Study challenges included limited responses precluding statistical analysis and the ability to submit incomplete responses due to sensitive subject matter. Conclusion Genetic technologies have shown significant advances and now allow early detection of those with hemophilia, including carriers. However, this study shows that experiences and knowledge of these technologies are still widely varied. As a result, hemophilia carriers may benefit from standardized educational materials which may compliment counselling provided by HTCs and may be useful for multigenerational knowledge dissemination. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

Perioperative Management for Congenital Factor XI Deficiency; A Systematic Review

Background: Congenital Factor XI (FXI) deficiency is the most common rare bleeding disorder, characterized by production defect of FXI. Bleeding manifestation is usually mild and associated with trauma or surgery. The treatment options during surgery include plasma, FXI concentrate, recombinant activated factor VII (rFVIIa), etc. This study aimed to investigate the efficacy of hemostatic control and thrombotic complications in patients with congenital FXI deficiency who underwent surgery or an invasive procedure.Methods: We conducted a systematic search in MEDLINE, EMBASE and CENTRAL database from inception to March 2016. We included the case reports and case series of patients with congenital FXI deficiency. Studies must report the perioperative treatment regimen, hemostatic outcome and thromboembolic complication. The pre- and post-FXI levels were collected. The primary outcome was the efficacy of hemostatic control and the safety outcome was thromboembolic complication.Results: There were 87 studies included in this review, involving 310 patients with congenital FXI deficiency. Median age was 49.5 years (range 0.3 to 94). Forty percent of the patients were male. Median baseline FXI level was 6.0% (range <1 to 75.0). FXI concentrate was the most common treatment (48.39%), following by plasma (21.61%), rFVIIa (12.90%) and others (FEIBA, DDAVP, tranexamic acid and no treatment; 17.1%). Hemostatic control was found to be good or excellent in 118 patients (88.06%) who had major surgery, 65 patients (92.85%) in minor surgery and 47 patients (97.91%) in dental procedure, Table 1. Thromboembolic events were reported in 7/150 (4.67%) patients treated with FXI concentrate and 4/34 (11.76%) patients treated with rFVIIa, Table 2. None of patients receiving plasma, FEIBA, DDAVP or tranexamic acid had thrombosis.Conclusion: Hemostatic control during perioperative periodwas achieved in majority of patients with congenital FXI. Peak plasma FXI should be obtained in patients treated with plasma or FXI concentrate with the target FXI of 60-70% for major surgery and 40-50% for minor surgery. With respect to the higher risk of thromboembolic complication, we recommend plasma over FXI concentrate and rFVIIa for perioperative treatment in patients with FXI deficiency. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Interim Canadian Data from a Prospective, Observational Study of Routine Clinical Use of a Von Willebrand Factor Concentrate (Wilate®)

Introduction:Von Willebrand disease (VWD) is the most common congenital bleeding disorder with a prevalence of symptomatic cases of 1 in 1,000. VWD is characterized by quantitative or qualitative abnormalities in von Willebrand factor (VWF), resulting in impaired haemostasis. To increase VWF levels, VWF concentrates are the only treatment option for approximately 20% of VWD patients for whom 1-deamino-8-D-arginine vasopressin (DDAVP) is not effective or is contraindicated. Wilate® (Octapharma AG, Lachen, Switzerland) is a high purity, double virus-inactivated, freeze-dried concentrate of VWF and FVIII. The ratio of VWF to FVIII is near the physiological value of 1:1 and is designed to simplify dosing and monitoring. Wilate®, initially approved in 2005 in Germany, is currently broadly approved worldwide for treatment of VWD and Hemophilia A. This non-interventional, prospective study in VWD patients was designed to collect information on the safety, tolerability and efficacy of Wilate® in routine clinical practice. We present the results of an interim analysis conducted in Canadian patients who received Wilate® in a routine clinical setting as prophylaxis, on-demand treatment and/or in a surgical setting. Methods:Ethics committee approval was obtained from all participating centres, and all VWD patients prescribed Wilate® from participating physicians were eligible for inclusion. Patients were excluded for the presence of VWF inhibitors, bleeding disorders other than VWD, a history of non-compliance, prohibitively difficult venous access, or the inability to follow study requirements. Routine clinical use of Wilate® for prophylaxis, on demand treatment of bleeding episodes, and prophylaxis for major and minor surgeries were documented. Parameters of routine clinical use are reported here and include exposure days, dosing, and number of infusions. Adverse drug reactions (ADRs), tolerability assessments, and haemostatic efficacy assessments are also reported. Results:Interim data from 13 patients, with a mean age of 45.6 (range 16 to 78 years), enrolled in participating Canadian centres was available for this analysis. Patients consisted of 3 males and 10 females, nine with type 1, three with type 2, and one with type 3 VWD. Two patients were treated for on-demand bleeding episodes, 2 were treated prophylactically, whereas 11 patients were treated for surgeries. A total of 1 051 000 IU Wilate® was infused in the thirteen patients with an average dose for all indications of 46 ± 9.7 IU/kg. Tolerability was 'excellent' in 284 of 285 (99.6%) assessed infusions. Hemostatic efficacy of Wilate® was assessed as 'excellent' or 'good' for all on-demand treatments of bleeding episodes. All 29 breakthrough bleeds, which were primarily GI bleeding, were treated successfully in one long-term prophylactic patient with severe VWD in 17 months. One other patient was treated for seventeen days following surgery and experienced no bleeding episodes. Eleven patients underwent 12 surgical procedures, one patient underwent 2 minor dental procedures, and 10 patients underwent ten major surgeries. In all 12 surgeries the haemostatic efficacy of Wilate® treatment was assessed as 'excellent.' No thrombotic events or severe ADRs were observed. Conclusion:This study is a part of ongoing pharmacovigilance of Wilate® and these interim observations support its safety and efficacy for VWD patients in routine clinical settings. In our Canadian cohort, under routine clinical conditions, bleed resolution, prevention, and tolerability were high. Disclosures Cosentino: Octapharma: Employment. James:CSL Behring: Research Funding; Octapharma: Research Funding; Biogen: Consultancy; Basalt: Consultancy; Bayer: Research Funding. Sholzberg:Shire (previously Baxter, Baxalta): Honoraria, Research Funding; Novonordisk: Honoraria.

Establishment of a bleeding score as a diagnostic tool for patients with rare bleeding disorders

IntroductionBleeding manifestations among patients with rare bleeding disorders (RBDs) vary significantly between disorders and patients, even when affected with the same disorder. In response to the challenge represented by the clinical assessment of the presence and severity of bleeding symptoms, a number of bleeding score systems (BSSs) or bleeding assessment tools (BATs) were developed. The majority of these were specifically developed for patients with more common bleeding disorders than RBDs. Few RBDs patients were evaluated with these tools and without conclusive results. MethodsA new BSS was developed using data retrieved from a large group of patients with RBDs enrolled in the EN-RBD database and from healthy subjects. These data included previous bleeding symptoms, frequency, spontaneity, extent, localization, and relationship to prophylaxis and acute treatment. The predictive power of this BSS was also compared with the ISTH-BAT and examined for the severity of RBDs based on coagulant factor activity. ResultsThis BSS was able to differentiate patients with RBDs from healthy individuals with a bleeding score value of 1.5 having the highest sum of sensitivity (67.1%) and specificity (73.8%) in discriminating patients with RBD from those without. An easy-to-use calculation was also developed to assess the probability of having a RBD. Its comparison with the ISTH-BAT confirmed its utility. Finally, in RBDs patients, there was a significant negative correlation between BS and coagulant factor activity level, which was strongest for fibrinogen and FXIII deficiencies. ConclusionThe use of this quantitative method may represent a valuable support tool to clinicians.

Development and validation of technical assays of von Willebrand disease in routine laboratory.

Von Willebrand disease (MW) is the most common constitutional bleeding disorders. It is caused by a quantitative or qualitative abnormality of the von Willebrand factor (VWF). The laboratory assessment of the disease combines a FVIII assay, and a determination of the antigen and activity of VWF. The analytical validation of VWF:Ag, VWF:Act, vWF:CB is reported in this work and demonstrates good test performance of all three assays, with a coefficient of variation lower than 10% for both the repeatability and reproducibility, stability with a deviation of less than 5% from the target value after six hours at room temperature. The dosages are linear through the following ranges: 2% to 346% for VWF:Ag, 3% to 170% for VWF:Act, and 0.07% to 259% for VWF:CB. The usual values determined on 32 control subjects are in the range of reference values published in the literature. However as the number of control samples tested is small, we will adopt the reference values of the literature of 50 to 200% in routine. The other functional test VWF:CB will be used in our daily practice to differentiate the type of 2M 2A type. However, given that the type 2M is extremely rare, we think it is rather aimed at specialized laboratories in which a large number of patients referred.

Von Willebrand disease - the 'Dos' and 'Don'ts' in surgery.

Von Willebrand disease (VWD) is the most common genetic bleeding disorder. VWD is caused by a deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates the initial adhesion of platelets at sites of vascular injury and binds and stabilises coagulation factor VIII (FVIII) in the blood. Prophylaxis of surgical bleeding in patients with VWD requires consideration of the individual situation, including the type of procedure and the bleeding rate, before decisions about treatment type, dose, duration and adjunctive therapy with antifibrinolytics or antithrombotic prophylaxis can be made. Although desmopressin (DDAVP)-stimulated release of endogenous VWD is an effective treatment strategy in many patients, plasma concentrates containing VWF are the preferred option for most patients undergoing surgical procedures. Recommendations for the management of surgery in patients with VWD are summarised, including the severity of VWD and the type of the surgical procedure.

Bleeding Assessment Tools: Limits and Advantages for the Diagnosis and Prognosis of Inherited Bleeding Disorders.

Bleeding assessment tools were first developed essentially as research tools, for the quantification of bleeding symptoms and the study of phenotype/genotype correlations. Interestingly, these tools have been proven useful also for clinicians diagnosing and treating bleeding disorders. The main advantage of these tools is the standardization of the diagnostic process, allowing the introduction of criteria with known specificity and sensitivity for the diagnosis of the most common mild bleeding disorders, particularly von Willebrand disease. This is important also for a rational approach to the laboratory diagnosis because for many mild bleeding disorders, a complex laboratory workup is required. Bleeding assessment tools should always be complemented by ancillary coagulation screening tests to exclude the presence of a bleeding disorder, however. Finally, bleeding severity assessed by such tools has been shown to correlate with the long-term probability of bleeding. Therefore, the bleeding assessment could become an important marker of disease severity.

Towards personalised therapy for von Willebrand disease: a future role for recombinant products.

von Willebrand disease (VWD) is reportedly the most common bleeding disorder and is caused by deficiencies and/or defects in the adhesive plasma protein von Willebrand factor (VWF). Functionally, normal VWF prevents bleeding by promoting both primary and secondary haemostasis. In respect to primary haemostasis, VWF binds to both platelets and sub-endothelial matrix components, especially collagen, to anchor platelets to damaged vascular tissue and promote thrombus formation. VWF also stabilises and protects factor VIII in the circulation, delivering FVIII to the site of injury, which then facilitates secondary haemostasis and fibrin formation/thrombus stabilisation. As a result of this, patients with VWD suffer a bleeding diathesis reflective of a primary defect caused by defective/deficient VWF, which in some patients is compounded by a reduction in FVIII. Management of VWD, therefore, chiefly entails replacement of VWF, and sometimes also FVIII, to protect against bleeding. The current report principally focuses on the future potential for "personalised" management of VWD, given the emerging options in recombinant therapies. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may soon change the way in which VWD is managed. In particular, we can envisage a personalised treatment approach using recombinant VWF, with or without recombinant FVIII, depending on the type of VWD, the extent of deficiencies, and the period and duration of treatment.

Evidence-based recommendations on the treatment of von Willebrand disease in Italy.

von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting both males and females. It arises from quantitative or qualitative defects of von Willebrand factor (VWF) and causes bleeding of mucous membranes and soft tissues. The aim of treatment is to correct the dual defect of haemostasis caused by the abnormal/reduced VWF and the concomitant deficiency of factor VIII (FVIII). This document contains evidence-based recommendations for the management of VWD compiled by AICE (the Italian Association of Haemophilia Centres). All the evidence supporting these recommendations are based on non-randomised comparative studies or case series, because randomised controlled clinical trials or meta-analyses are not available for this disease. Desmopressin (DDAVP) is the treatment of choice for patients with type 1 VWD with FVIII and VWF levels of 10 U/dL or more, while VWF/FVIII concentrates are indicated for those who are unresponsive or insufficiently responsive to DDAVP (severe type 1, type 2 and 3 VWD). VWF concentrates devoid of FVIII, not yet licensed in Italy, may be considered for short-term prophylaxis in elective surgery or for long-term secondary prophylaxis.

Hemophilia in Iran

Background: Hemophilia A (HA) and B (HB) are common bleeding disorders, Iran having the ninth largest such population in the world. A considerable number of studies have been performed on different aspects of their disorder.Objective: The aim of the study was to gather all obtainable data about Iranian patients with HA and HB, including molecular studies, clinical presentations and treatment, and development and management of patients with inhibitor, to help better understand the disease and its management in other parts of the world.Methods: For this review study, we searched MEDLINE and Scientific Information Database for English and Persian sources until 2015.Results and discussion: There are 5369 patients with HA and HB in Iran among which 4438 patients have HA. About one-fifth of HA patients' genes were analyzed and their underlying defects detected. Hemarthrosis, epistaxis, ecchymosis, and post-dental extraction bleeding are the most common clinical presentations. Bleeding was mainly managed by on-demand replacement therapy with factor VIII/factor IX (FVIII/FIX) concentrates or cryoprecipitate in HA, and fresh frozen plasma in HB in the absence of factor concentrate. Mean per capita for FVIII in HA patients is 1.56 IU, which is higher than the global per capita mean. However, mean per capita for FIX (0.24 IU) is lower than the global mean but highest among eastern Mediterranean countries. Replacement with plasma-derived components has led to infection in a large number of patients as well as inhibitor development against exogenous infusion of coagulation factors. According to a World Federation of Hemophilia survey, 223 HA and 6 HB patients in Iran have developed inhibitor and have been mainly managed by recombinant FVII (rFVIIa) and activated prothrombin-complex concentrate.Conclusion: Although this study was performed in Iranian patients, the large number thereof gives confidence that the results can be used more widely for other countries, especially in the developing world.

Heavy Menstrual Bleeding as a Common Presenting Symptom of Rare Platelet Disorders: Illustrative Case Examples

Heavy menstrual bleeding (HMB) is a common symptom in patients who present to the obstetrician-gynecologist or adolescent medicine specialist and might result from an underlying inherited bleeding disorder. Whereas relatively common bleeding disorders such as von Willebrand disease are often included in standard laboratory assessments, rarer platelet function disorders can be challenging to diagnose. Additionally, HMB can be a particularly difficult symptom to manage in adolescents with platelet function disorders, and it is associated with decreased quality of life. We review the diagnostic and management issues of patients with platelet function disorders through the presentation of 2 patient case reports, with a focus on a diagnosis of Glanzmann thrombasthenia, an inherited qualitative disorder that affects platelet function. Whereas the first patient presented to the emergency department before the diagnosis of a bleeding disorder and required a hematologic referral and extensive laboratory assessments, the second patient had been diagnosed with Glanzmann thrombasthenia as a child but experienced severe management challenges at the onset of menarche. In both patients, collaboration between the obstetrician-gynecologist or adolescent medicine specialist and the hematologist was critical for achieving acute management of the bleeding symptoms and for ensuring optimal long-term disease management. Together, these cases highlight the importance of properly identifying females with HMB who might have an undiagnosed bleeding disorder and of consulting with a hematologist to determine an appropriate management plan throughout all life stages.

Von Willebrand factor for menorrhagia: a survey and literature review.

von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

On-Rate Switching under Force Increases the Binding of von Willebrand Factor A1 to GPIbα

Alterations in flow during bleeding trigger the von Willebrand factor (VWF) A1 domain to bind to glycoprotein Ibα (GPIbα) on platelets, initiating blood clotting. Using a laser tweezers and a Receptor and Ligand in a Single Molecule (ReaLiSM) construct, we find that force can switch A1 and/or GPIbα to a different state with a faster on-rate; this provides an additional mechanism for activating VWF binding to platelets. Mutations in VWF induce von Willebrand disease (VWD), a common human bleeding disorder. Our results show that force escalates the effects of VWD mutations with respect to on-and off-rates, explaining pathophysiology. Using the effective concentration of receptor and ligand in ReaLiSM to convert single molecule kon (units of s−1) to bulk phase kon (units of s−1M−1) allows the calculation of an equivalent binding affinity. We find that using extrapolated, zero-force kon and koff values from the low-force state of the bond to calculate the binding affinity provides remarkably good agreement with bulk phase measurements.

Common bleeding disorders affecting individuals with Hereditary Hemorrhagic Telangiectasia.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder affecting vasculature in different organ systems; seen at a rate of approximately 1:5000 in North America. Complications, with significant increases in health service utilization, arise from bleeding and shunts, and are particularly problematic in the lung and liver. Although these patients tend to chronically bleed from the GI tract and nasal cavities, a single bleed from arterio-venous malformations in the lungs or brain can have serious health implications and may be fatal. Bleeding due to vascular wall fragility in HHT patients can be further complicated with a concomitant bleeding disorder. The proportion of adult patients seen in the Edmonton HHT center with a concomitant bleeding disorder, as assessed by blood test results for Factor VIII and related factors (Ristocetin Cofactor), Factor IX and Factor XI, was determined in a retrospective, single centre study. Of 77 individuals with HHT, four had below normal values of von Willebrand Factor, Ristocetin Cofactor or Factor VIII. Two patients had laboratory parameters diagnostic of a bleeding disorder, accounting for 2.6% of confirmed HHT subjects. These results indicate that establishing screening for bleeding disorders in HHT centers is important in managing bleeding symptomatology. In individuals with HHT, the presence of a second bleeding disorder can have significant clinical implications on patient management and health care utilizations. This paper highlights areas that need to be reviewed with respect to best practice protocols for the management of HHT patients.

FREQUENCY AND DEGREE OF CHRONIC ARTHROPATHY IN HEMOPHILIA A PATIENTS ON PROPHYLACTIC AND ON-DEMAND TREATMENT

hemophilia A is the most common congenital bleeding disorder caused by a deficiency in coagulation factor VIII activity, characterized by a marked bleeding tendency. It is inherited recessively. The most common complication of the disease is chronic arthropathy. In the prophylactic treatment regimen, the subjects receive preventative F VIII infusions every second day or three times a week. In an on-demand regimen, bleeds are treated as they occur. Analysis of the frequency and degree of chronic hemophilic arthropathy in patients with moderate and severe hemophilia A. Analysis of involvement of individual joints, and their score values by the treatment regimen (prophylaxis vs. on-demand treatment.) The study included 23 patients - 15 patients on 'on-demand' regimen and 8 patients who had prophylaxis, all being treated at the Clinic of Hematology and Clinical Immunology, Clinical Center Nis. In the assessment of frequency of complications we used descriptive statistics: the number, proportion and mean. The comparison of arithmetic means of the two samples was performed using the t-test. The comparison of frequency values was performed using the chi-square test or Fisher's test. In the group without prophylaxis, the knee and hip were the most commonly affected sites (73.33% and 53.33%), and in the group with prophylaxis, the elbow joint was mostly affected (37.50%). The knee was statistically more often affected in patients without prophylaxis compared to those on prophylaxis. The knee score had the highest value in both groups. It was statistically significantly higher in patients without prophylaxis compared to those on prophylaxis. The hip score was the second highest value in the examined groups, the third was the elbow joint score, followed by the ankle score, and the lowest score was observed for the shoulder joint. Elbow and ankle scores were statistically significantly higher in patients without prophylaxis compared to those on prophylaxis. Chronic arthropathy is the most common complication in patients with severe and moderate Haemophilia A, with maximum involvement of the knee joint in both groups of patients (with or without prophylaxis), but with a statistically significantly higher score in patients without prophylaxis.

Evaluation of a von Willebrand factor three test panel and chemiluminescent-based assay system for identification of, and therapy monitoring in, von Willebrand disease

von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing of VWD has important management implications and requires a wide range of tests, including VWF antigen (VWF:Ag) and various activities, involving differential identification of qualitative vs quantitative VWF defects. We have assessed a new hemostasis instrument, the chemiluminescent assay based ACL AcuStar™, and an associated HemosIL AcuStar three test panel comprising VWF:Ag, VWF ristocetin cofactor (VWF:RCo) and VWF collagen binding (VWF:CB) (Instrumentation Laboratory, Bedford, Ma. USA) for ability to identify VWD, to help provisionally type VWD, and for potential use in therapy monitoring. This test system was compared to previously evaluated and validated test systems including VWF:RCo on CS-5100 and BCS analyzers, the new Siemens INNOVANCE assay (VWF Ac) on CS-5100, and VWF:Ag and VWF:CB assays performed by automated ELISA. We employed a large total sample test set (n=535) comprising plasma and platelet-lysate samples from individuals with and without VWD, some on treatment, normal plasmas, and normal and pathological controls. We also evaluated desmopressin (DDAVP) responsiveness, plus differential sensitivity to reduction in high molecular weight (HMW) VWF. The chemiluminescent test panel (VWF:Ag, VWF:RCo, VWF:CB) showed good comparability to similar assays performed by alternate methods, and broadly similar data for identification of VWD, provisional VWD type identification, DDAVP and VWD therapy, and HMW VWF sensitivity, although some notable differences were evident. The chemiluminescent system showed best low level VWF sensitivity, and lowest inter-assay variability, compared to all other systems. In conclusion, we have validated theACL AcuStar and the chemiluminescent HemosIL AcuStar VWF test panel for use in VWD diagnostics, and have identified some favorable characteristics that may improve the future diagnosis of VWD.