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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1226-1226
Author(s):  
Deepa Ranjani Jayakody Arachchillage ◽  
Tina Biss ◽  
John Hanley ◽  
Kate Talks
Keyword(s):  
Laboratory Tests ◽  
Conflicts Of Interest ◽  
Bleeding Disorder ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Number Of Patients ◽  
Abnormal Bleeding ◽  
Bleeding Score

Abstract Abstract 1226 The 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)17–57 Compared 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.

Factor XI (P. T. A.) Deficiency with No Hemorrhagic Symptoms

1964 ◽  
Vol 11 (01) ◽  
pp. 187-194 ◽  
Author(s):  
Margaret Todd ◽  
Irving S. Wright
Keyword(s):  
Surgical Procedures ◽  
Autosomal Recessive ◽  
In Vitro Tests ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Coagulation Defect ◽  
Abnormal Bleeding ◽  
A Minor

SummaryA case has been presented, which has been diagnosed as a familial deficiency of Factor XI (PTA).The patient with Factor XI deficiency has a gross coagulation defect as demonstrated by numerous in vitro tests. However, to date neither the proband, his mother, nor his sister, who share the same deficiency, has shown any evidence of an abnormal bleeding tendency, even when subjected to repeated surgical procedures. These patients have a minor PTA deficiency and are heterozygous for the deficiency, which is transmitted as an autosomal recessive.

A Relatively Low Frequency of Bleeding in Patients with Severe Factor XI Deficiency Who Undergo Surgery Involving Tissues with Low Fibrinolytic Activity Supports on Demand Rather Than Prophylactic Use of Plasma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4036-4036
Author(s):  
Ophira Salomon ◽  
David M. Steinberg ◽  
Uri Seligsohn
Keyword(s):  
Fibrinolytic Activity ◽  
Oral Surgery ◽  
Low Frequency ◽  
Fresh Frozen Plasma ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
On Demand ◽  
Number Of Patients ◽  
Fresh Frozen

Abstract Severe factor XI (FXI) deficiency is an injury related bleeding tendency. Fresh frozen plasma (FFP) or FXI concentrate are usually used for achieving hemostasis in such patients undergoing surgery but this can lead to inhibitor formation in 33% of patients with FXI level <1 U/dL (Blood101:4783, 2002). Based on observations in a limited number of patients with severe FXI deficiency, we previously suggested that surgery at tissues with known fibrinolytic activity is accompanied by bleeding more frequently than in other sites (NEJM325:153, 1991). In this study we retrospectively assessed the frequency of post surgical bleeding in 165 unrelated patients with severe FXI deficiency who were not treated by hemostatic means. Criteria for bleeding included local hematoma, need for surgical arrest of bleeding, or use of blood components. Bleeding occurred in 7/57 (12.3%) patients operated at tisues with low fibrinolytic activity, and in 29/48 (60.4%) patients operated at fibrinolytic sites (Table). Bleeding following circumcision (a non-fibrinolytic site) was accompanied by bleeding only in 1/64 (1.6%) and following oral surgery in 55/110 patients (50%). The relatively low frequency of bleeding following surgery at non-fibrinolytic sites advocates on demand rather than prophylactic replacement therapy when such surgery is performed. SITE OF SURGERY N BLEEDERS % BLEEDERS Non-fibrinolytic Appendicectomy 22 1 1.6 Gastric 3 0 0 Cholecystectomy 5 1 20 Herniotomy 13 3 23 Hysterectomy 5 2 40 Orthopedic 9 0 0 Fibrinolytic Tonsillectomy 33 20 60.6 Nose 12 7 58.3 Prostatectomy 3 2 66.6 Circumcision 64 1 1.6 Oral Tooth extractions 100 49 49 Gum 10 6 60

Thrombin Generation Test Can Predict Bleeding Tendency In Patients With Severe Factor XI Deficiency

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3600-3600 ◽  
Author(s):  
Tami Livnat ◽  
Uriel Martinowitz ◽  
Rachel Mansharov ◽  
Zivelin Ariella ◽  
Ophira Salomon
Keyword(s):  
Thrombin Generation ◽  
Prophylactic Treatment ◽  
Conflicts Of Interest ◽  
Peak Height ◽  
Activity Level ◽  
Bleeding Tendency ◽  
Bleeding Disorders ◽  
Normal Range ◽  
Factor Xi ◽  
Factor Xi Deficiency

Abstract Introduction Factor XI (FXI) is a rare bleeding disorder defined as severe deficiency when FXI activity level is less than 20IU/dL. Unlike hemophilia A or B, patients with severe FXI deficiency do not bleed spontaneously and their bleeding tendency is unpredictable and poorly correlated with FXI level. Therefore, almost all patients with severe FXI deficiency are being treated similarly unrelated to their inert bleeding tendency. Lately there is a growing interest in introducing global coagulation tests to assess the risk of bleeding in trauma patients as well as in patients with congenital bleeding disorders. Thrombin generation (TG) test is a global assay that can provide information regarding hemostasis in healthy individuals or in patients with congenital and acquired bleeding disorders. Our group had previously shown that recalcification induced TG is a useful tool to determine the optimal dose of recombinant factor VIIa for patients with severe FXI deficiency and inhibitors going through major surgery (Livnat et al. Thromb Haemost 2009). Aim In the present study we aimed to characterize the capability of TG to serve as an ideal tool to define upfront bleeders and non-bleeders among FXI deficient patients and find the optimal conditions of TG that could distinguish between bleeders and non-bleeders thus eventually leading to efficient personalized treatment. Methods Case control study composed of 16 unrelated patients with FXI levels range >1-8dL-1and 14 healthy controls. For TG assay blood was taken from all participants simultaneously in both buffered citrate and corn trypsin inhibitor (CTI) tubes after obtaining informed consent. TG was performed in platelet poor plasma (PPP) in the presence of 4 µM phospholipids and initiated by recalcification in the presence and absence of 1pM tissue factor (TF). Three TG parameters were analyzed: lag time, thrombin peak and endogenous thrombin potential (ETP). Results Table 1 summarizes FXI activity, FXI genotype, thrombin peak height and bleeding status (i.e, bleeding following challenges when prophylactic treatment was not given) of patients in the study group. As expected, FXI levels poorly correlated with bleeding tendency. Good correlation between FXI levels, bleeding tendency and TG peak height was found when blood was taken in citrated tubes and not in CTI containing tubes. While the normal range of peak height in recalcification-induced TG (without TF) was 421±161 nM, no TG was initiated with recalcification in PPP of FXI patients with less than 1%. FXI levels 2-4% were sufficient to induce TG with recalcification but thrombin peak height was remarkable lower in comparison to controls. In FXI levels above 5%, the thrombin peak height induced by recalcification varied between low to normal range. Interestingly, when TG was initiated by 1pM TF the TG peak of non-bleeders reached normal values (normal peak height in the presence of 1pM TF=411±121), while in the bleeders the peak was reduced unrelated to FXI levels (range 74-205). Conclusions In summary TG induced by recalcification in the presence of low TF but not when performed in CTI tubes may efficiently distinguish between bleeders and non-bleeders in FXI deficient patients going through major trauma unrelated to patients' FXI level. This observation permits to consider less aggressive prophylactic treatment to patients with reduced risk for bleeding thus lowering the risk of thrombosis due to over treatment. Disclosures: No relevant conflicts of interest to declare.

Von-Willebrand-Syndrom Typ 1 und Schwangerschaft

2011 ◽  
Vol 31 (S 01) ◽  
pp. S11-S13 ◽  
Author(s):  
J. Oppermann ◽  
A. Siegemund ◽  
R. Schobess ◽  
U. Scholz
Keyword(s):  
Clinical Presentation ◽  
Bleeding Disorder ◽  
Bleeding Tendency ◽  
Laboratory Findings ◽  
Mucous Membranes ◽  
Von Willebrand

SummaryThe von Willebrand-Jürgens syndrome (VWJS) type 1 is a common hereditary bleeding disorder with a bleeding tendency located especially in the mucous membranes. Women suffering from VWJS type 1 show menorrhagia and prolonged postoperative bleedings. During pregnancy the clinical presentation varies by the increase of the von Willebrand factors.In this article the laboratory findings and the clinical presentation of patients with VWJS during pregnancy was examined. The necessity of interventions during pregnancy and at the time of delivery was under consideration.

The Use of Factor XI Concentrates (Hemoleven, LFB) in Patients with Congenital Factor XI Deficiency and a Known Bleeding Tendency.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1796-1796
Author(s):  
Vickie McDonald ◽  
Savidge F. Geoffrey ◽  
Savita Rangarajan ◽  
Mike Mitchell
Keyword(s):  
Fresh Frozen Plasma ◽  
Incidence Rates ◽  
Treatment Modalities ◽  
Bleeding Tendency ◽  
Normal Range ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Unit Dose ◽  
The Mean ◽  
Congenital Factor

Abstract Traditional treatment modalities for FXI deficiency (UK prevalence 400 cases) include antifibrinolytics, desmopressin, fresh frozen plasma (FFP) and FXI concentrates but there has been reluctance to use FXI concentrates because of reported incidence rates of thrombosis up to 10%. Concerns over the safety and efficacy of FFP, with additional viral inactivation steps possibly leading to reduced FXI recoveries, have led us to increase our use of FXI concentrates. We aimed to assess the indications, dosage, recovery, efficacy and safety of Hemoleven, a plasma derived, purified and virally inactivated FXI concentrate, which also contains heparin and antithrombin, in patients with congenital factor XI deficiency. A retrospective study was performed using hospital notes and laboratory records of all patients who had received Hemoleven over a 2-year period. Eleven patients (6 male, 5 female) had been treated with a median age of 38 years (range 7–74) and mean baseline FXI:C levels of 25.4U/dl (3–50). All patients received Hemoleven as prophylaxis for surgery or dental work and had all previously had excess bleeding when surgically challenged. One patient died of a condition unrelated to FXI treatment. Pre- and post-FXI:C levels were available for a total of 60 treatment episodes of which 25 were 1000-unit doses and 35 were 2000-unit doses. The mean increase in FXI:C per 1000-unit dose was 25.4 U/dl (12.4–43.9) while the mean increase in FXI:C per 2000-unit dose was 50.5 U/dl (11.8–106.5). This is consistent with the manufacturer’s data. Ten minute post infusion FXI:C levels were above the normal range (73–133 U/kg) in 8% of patients given 1000 units and 11% of patients given 2000 units but below the normal range in 24% of patients who received 1000 units and 20% of patients who received 2000 units. 90% of treatment episodes led to FXI:C levels above the usual treatment target of 65 U/dl. Genetic analysis of 9/11 patients showed that 2 were homozygous (one type II and one type III), 6 were heterozygous for other recognised mutations and one had no mutation identified but apparent absence of RNA from one allele demonstrated in a relative by qRT-PCR. No excess bleeding or inhibitor development was recorded even in one patient who had had a poor haemostatic response with FFP. There were no episodes of arterial or venous thrombotic complications within this group and no clinical or laboratory evidence of DIC following treatment. In summary, treatment with factor XI concentrates gave consistent increments in FXI:C at the doses given and achieved good haemostasis with no episodes of thrombosis in this study, even in patients over the age of 60y. While the risk of prion transmission is still unknown, use of FXI concentrates is not associated with the risks of fluid overload and TRALI that are seen with FFP. We acknowledge that the study includes small numbers of patients however the cohort of patients with a bleeding diathesis in this condition is small. We conclude that Hemoleven appears to be an effective and reliable treatment for patients with FXI:C deficiency but should be given in the context of FXI:C level monitoring in order to detect those patients who may develop high levels and possible thrombosis.

A G>A Transition in the Non-Coding Exon 1 of the Factor XI Gene as the Cause of Factor XI Deficiency in Three Afro-Caribbean Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1788-1788
Author(s):  
Michael J. Mitchell ◽  
Letian Dai ◽  
Anwar Alhaq ◽  
Geoffrey F. Savidge
Keyword(s):  
Base Change ◽  
Clinical Severity ◽  
Molecular Defect ◽  
Polymorphism Analysis ◽  
Bleeding Tendency ◽  
Translation Efficiency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Plasma Factor ◽  
Exon 1

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of 9%, associated with two common founder mutations E117X (Type II) and F283L (Type III). However, factor XI deficiency is found in all ethnic groups, with causative mutations being highly heterogeneous - mutations having been described in all exons with the exception of the non-coding exon 1. In a study of >120 ethnically diverse factor XI deficient patients, three patients of Afro-Caribbean origin were found to be heterozygous for a G>A transition at nucleotide −53 within exon 1 of the factor XI gene. All three patients showed a low FXI:C on at least 3 different occasions (SM[female] 44.3–57.1, AB[female] 42.3–51.2 and GA[male] 70.3–72.9, Range 76–136u/dl). The 2 female patients were both reported to have a lupus anticoagulant which may explain the lower levels seen, although a lupus screen was negative. No variation within the coding sequence of the factor XI gene was detected. Two of the patients were heterozygous for the −403 G>T promoter polymorphism, whilst the remaining patient was homozygous for the −403 T allele and heterozygous for the −273 C>G polymorphism. Analysis of >50 factor XI alleles in patients of Afro-Caribbean origin failed to detect this base change in individuals with normal factor XI levels. Purine-rich sequences, such as that in exon 1 affected by the −53 G>A substitution, are known to form extremely stable minihairpin loops. These sequences /structures have been shown to be important as splicing enhancers and in mRNA stability, particularly in making them more resistant to nucleases. Within the 5′ untranslated region (5′-UTR) of genes they have been demonstrated to be important in modulating translation efficiency. The -53 G>A substitution is located just 10 bases prior to the start of the factor XI mRNA and any of these mechanism could potentially explain the causative nature of this change. The -53 G>A substitution is predicted to cause ‘slippage’ within the postulated minihairpin loop, potentially making it unstable. Further work is on-going to try and prove and explain the causality of this mutation. We speculate that the -53 G>A base change affects the normal processing of factor XI mRNA and, possibly in combination with the promoter polymorphisms, results in a mildly reduced plasma factor XI level.

Quantitation of Bleeding Symptoms in Children with von Willebrand Disease (VWD) or a Platelet Function Disorder: Use of a Standardized Pediatric Bleeding Score.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2137-2137 ◽  
Author(s):  
T.T. Biss ◽  
V.S. Blanchette ◽  
M. Bowman ◽  
D.S. Clark ◽  
M. Silva ◽  
...  
Keyword(s):  
Platelet Function ◽  
Dense Granule ◽  
Von Willebrand Disease ◽  
Number Of Patients ◽  
Kingston General Hospital ◽  
Bleeding Score ◽  
Sick Children ◽  
Bleeding History ◽  
Score Range

Abstract Obtaining an accurate bleeding history is an essential step in the diagnosis of a bleeding disorder, which is often made during childhood. A bleeding history is usually taken in an informal manner, with the interpretation of the responses dependent on the experience of the observer. The development of standardized bleeding questionnaires has improved objectivity and allowed the determination of quantitative scores according to the severity of mucocutaneous bleeding. In adults, using the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Questionnaire for Diagnosis of Type 1 VWD, a bleeding score of >3 in males and >5 in females is considered abnormal (Rodeghiero et al., J Thromb Haemost2005:3;2619). Children have often not been exposed to hemostatic challenges and may have low scores despite significant bleeding disorders. Symptoms specific to childhood, such as post-circumcision bleeding, umbilical stump bleeding and cephalohematoma may be of greater significance in this patient group. Thus, we adapted the ISTH Bleeding Questionnaire for use in pediatrics, with a symptom-specific grade of -1 to 4 (Tosetto et al., J Thromb Haemost2006:4;766). Bleeding scores were determined by interview of parents/children for 80 children with a previous diagnosis of VWD or a platelet function disorder at The Hospital for Sick Children, Toronto, or Kingston General Hospital, Kingston. 62 children had a diagnosis of VWD and 18, a disorder of platelet function (Glanzmann thrombasthenia: 3; dense granule defect: 2; MYH9-related thrombocytopenia: 2; Hermansky-Pudlak syndrome: 1; unspecified: 10). 45 children were female and 35, male (median age: 10 yrs (range: 9 mo-17 yrs)), with a median age of females of 12 yrs (range: 0–17) and of males, 9 yrs (range: 1–17). Bleeding scores ranged from 0–28 (median: 7), with a median score in females of 7 and in males, 8. Bleeding scores according to diagnosis and age are shown in Tables 1 and 2, respectively. The most frequent reasons for a positive score of ≥2 were epistaxis (43% of patients), bleeding from minor wounds (38%), bleeding after dental extraction (31%) and excessive bruising (26%). Menorrhagia requiring treatment occurred in 47% of menstruating females. Bleeding from the umbilical stump, post-circumcision bleeding and cephalohematoma were reported in 10%, 6% and 4% of patients, respectively. In summary, we have used a standardized bleeding questionnaire, adapted for use in pediatrics, with an accompanying score to quantify bleeding symptoms in children with confirmed VWD or a platelet function disorder. Bleeding scores were lowest in the youngest age group (0–3 yrs), and were slightly higher in males than in females. Bleeding occurred early in childhood, i.e. post-circumcision bleeding and bleeding from the umbilical stump. This standardized pediatric bleeding questionnaire/score may be useful in clinical practice in the assessment of children presenting with symptomatic bruising and bleeding. Diagnosis Type 1 VWD Type 2 VWD Type 3 VWD Platelet function disorder Number of patients 48 8 6 18 Median bleeding score (range) 6 (0–18) 10 (0–17) 14 (9–28) 9 (1–19) Age (years) 0–3 4–6 7–9 10–12 13–15 16–18 Number of patients 7 13 18 16 14 12 Median bleeding score (range) 2 (0–9) 10 (0–16) 6 (0–19) 9.5 (1–28) 6 (2–18) 12 (6–21)

The Power of a Standardized Bleeding Score in Diagnosing Pediatric Type 1 Von Willebrand Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1293-1293
Author(s):  
Paul D Marcus ◽  
Kidan G Nire ◽  
Linda Grooms ◽  
Jennifer Klima ◽  
Sarah O'Brien
Keyword(s):  
Platelet Function ◽  
Predictive Value ◽  
Care Setting ◽  
Tertiary Care ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
The Mean ◽  
Bleeding Score ◽  
Von Willebrand

Abstract Abstract 1293 Poster Board I-315 INTRODUCTION Type I von Willebrand disease (VWD) is the most common inherited bleeding disorder. Repetitive testing of von Willebrand factor (VWF) levels is necessary before the diagnosis can be safely ruled out, as VWF levels fluctuate in response to genetic and environmental factors. A predictive bleeding score (BS) could reveal individuals that may benefit from repetitive testing and those for whom repetitive testing is unlikely to be of benefit. While a standardized questionnaire (the Vicenza score) was developed to evaluate hemorrhagic symptoms, it was never prospectively validated for a pediatric population in a tertiary care setting. SUBJECTS The study targeted children, ages 0 to 17 years, referred to the Hemostasis and Thrombosis Center (HTC) of Nationwide Children's Hospital for a coagulation evaluation as a result of bleeding symptoms, family history of a bleeding disorder and/or abnormal coagulation labs found during pre-operative screening. Children were excluded if they had a previously diagnosed bleeding disorder, if their caregiver did not speak English or if the child did not undergo VWF:Ag and VWF:RCo testing. METHODS Prior to the diagnosis or exclusion of a bleeding disorder in the child, caregivers consented to answer the questionnaire over the telephone. Descriptions of the Vicenza score are available online (http://www.euvwd.group.shef.ac.uk/bleed_score.htm). LABORATORY TESTING A single VWF:Ag or VWF:RCo <30 IU/dL was classified as “Definite Type 1 VWD” while levels from 30-50 IU/dL were classified as “Low VWF” (http://www.nhlbi.nih.gov/guidelines/vwd). Platelet function analysis (PFA-100) screened for platelet function defects, with some patients undergoing follow-up platelet aggregation studies and/or platelet electron microscopy. Laboratory studies from other institutions were excluded from analysis. Patients' medical records were reviewed after hematologic evaluation, and the resultant data was analyzed with STATA 10.1 (Stata Corp., College Station, TX). RESULTS A total of 104 children (52 females and 52 males) with a mean age of 7.53 years (range 1 month to 17 years) were included. At least one hemorrhagic symptom was present in 99 of the 104 children (95%) with the mean number of symptoms being 2.87 (range 0 to 7). The mean Vicenza score was 3.24 (range -1 to 13). Of the 104 children, 8 met criteria for “Definite Type 1 VWD,” 23 met criteria for “Low VWF,” 14 were diagnosed with a “Platelet Function Defect,” and 2 children had bleeding secondary to Ehlers Danlos syndrome. Children with non-bleeding disorders (e.g. Factor XII deficiency) or no laboratory evidence of a bleeding disorder were classified as “No Bleeding Disorder.” In general, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive diagnostic likelihood ratio of the bleeding questionnaire demonstrated poor predictive value in our patient population with the exception of high specificity in ruling out “Definite Type 1 VWD” (Table). The NPV was comparably high with both qualitative (>2 bleeding symptoms) and quantitative (BS ≥2) criteria. CONCLUSIONS The Vicenza score, previously validated in adults and in a pediatric primary care setting, appears to have limited predictive value in a pediatric tertiary care setting when evaluating patients with platelet function defects or low VWF levels. While the Vicenza score has a high NPV to exclude “Definite Type 1 VWD,” the use of simpler qualitative criteria is similarly predictive. Disclosures No relevant conflicts of interest to declare.

The Complete Type I VWD Cohort Of The Zimmerman Program For The Molecular and Clinical Biology Of VWD - Phenotypic Assignment, Mutation Frequency, and Bleeding Assessment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 332-332 ◽  
Author(s):  
Robert R. Montgomery ◽  
Pamela Christopherson ◽  
Daniel B. Bellissimo ◽  
Joan Cox Gill ◽  
Sandra L. Haberichter ◽  
...  
Keyword(s):  
Family Members ◽  
Normal Range ◽  
The Usa ◽  
Abnormal Bleeding ◽  
Bleeding Score ◽  
Clinical Biology ◽  
Severe Type ◽  
Index Cases ◽  
Normal Controls

Abstract The Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCBVWD) is an NIH Program Project for the study of VWD in the USA and collaboration with ongoing studies in Canada and the University of Sheffield. Study subjects were recruited from 9 Primary Clinical Centers and 21 Secondary Clinical Centers across the USA and had to have the prior diagnosis of VWD on an intention to treat basis. We recruited 651 index cases, 2017 family members, and 247 normal controls. Of the index cases 152 had type 2 or 3 VWD or other variants and not part of this report. The remaining 499 represents the now completed Type 1 VWD cohort. All 2915 study subjects underwent extensive laboratory testing including VWF:Ag, VWF:RCo, VWF multimeric analysis, FVIII activity, VWFpp, and VWF:CB (collagen binding), blood typing, and VWF linkage analysis. A detailed quantitative bleeding score (BS) was also performed on all 2915 individuals. Index cases had full length VWF sequencing with mutation confirmation and exclusion in family members. When indicated VWF:F8B (FVIII binding), VWF:PB (platelet binding to GPIb), VWF:IbCo (spontaneous binding to modified GPIb in absence of ristocetin), and repeat VWF testing in a second laboratory by different methods. When possible, historical laboratory results obtained at the time of initial diagnosis were obtained and entered into our Investig-8 Database. Based upon clinical laboratory studies and phenotypic assignment, this cohort was found to include 232 type 1 VWD (VWF:Ag or VWF:RCo <40 IU/dL including 66 type 1C or severe type 1 VWD); 93 low-VWF (LVWF with lab studies between 40 IU/dL and the lower end of the normal range); 119 type 1H (historical levels below the normal range but not substantiated in current testing); and 55 individuals that tested within the normal range and did not have historic levels that were low. Full-length VWF sequencing was performed on all index cases and sequence variations (SVs) were identified, and where possible, compared to clinical phenotypes reported in the Sheffield Database. SVs were identified in 53% of the Type 1 VWD cohort (excluding those that were normal on testing without abnormal historic results). Of the 232 Type 1 VWD with VWF levels <40, 74% had SVs. In further analysis of this group, 100% of severe type 1, and 85% of type 1C had SVs. Looking at this in the type 1 with VWF:Ag <40 IU/dL by level of VWF:Ag, 87% of those 1 with VWF:Ag of 2-10, 93% with VWF:Ag 11-20, 71% with VWF:Ag of 21-30, 67% with VWF:Ag of 31-40, and 52% with VWF:Ag of >40 had SVs. The milder phenotypes demonstrate SVs in 39% of the LVWF subjects and 30% of the Type 1H subjects. In the individuals entered into the study as VWD subjects that on central testing had normal levels of VWF on entry into the study and did not have an abnormal historic VWF determination, only 22% had SVs. A similar approach was undertaken to compare the quantitative BS using the ISTH Bleeding Assessment Tool. For this analysis, a score of 5 or greater was considered abnormal without regard to age or sex. Abnormal BS were identified in 63% of those with VWF:Ag of 2-10, 66% of those 11-20, 64% of those 21-30, 48% of those 31-40, and 58% of those >40. In LVWF subjects, 52% had abnormal BS and in Type 1H subjects 57% were abnormal. Based upon a similar laboratory analysis, all 2017 family members underwent phenotypic assignment and were found to either be affected or unaffected family members. 713 were phenotyped as being an affected family member and 1296 as unaffected family members. Abnormal bleeding scores were identified in 38% of affected family members and 19% of unaffected family members. This report summarizes some of the results on the completed Type 1 VWD cohort that was part of the ZPMCBVWD. All 2915 subjects (including index cases, family members, affected family members and normal controls) underwent extensive laboratory testing and phenotype assignment. Of the 499 subjects in the Type 1 VWD cohort, 325 had low VWF and 232 had VWF levels <40 IU/dL. Based on the drop of SV frequency, the level of VWF <40 may provide a possible demarcation to define VWD. In this study the frequency of abnormal bleeding score was not helpful in further defining this critical level for diagnosis - possibly because the bleeding score was ascertained at the entry into the study rather than at the time of diagnosis as done in earlier studies. Further analysis of this cohort can be expected to shed further understanding of the molecular and clinical biology of VWD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Calr Mutational Status in Egyptian Patients with Myeloproliferative Neoplams

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5388-5388
Author(s):  
Eman A. Soliman ◽  
Samah I. El-Ghlban ◽  
Abdelaleem H. Abdelaleem ◽  
Sherin Abdel-Aziz ◽  
Sameh Shamaa ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Response To Therapy ◽  
Hcv Infection ◽  
Number Of Patients ◽  
Significant Difference ◽  
Egyptian Patients ◽  
Calr Mutations

It has been known that the insertion/deletion mutation of CALR gene is the second deriver mutation in myeloproliferative neoplasm (MPN) of essential thrompocythemia (ET) and primary myelofibrosis (PMF). As the molecular workup has been incorporated for the prospective screening and diagnosis of MPN in our Oncology Center. An Egyptian 87 cohort of patients with non-mutated JAK2 (58 ET and 29 MF) were investigated using polymerase chain reaction (PCR) as a pilot study. We found that 37 out of 87 patients (42%) were carrying CALR mutations (30 out of ET (52%) and 7 out of MF (24%)). Sanger sequencing was used to determine the type of CALR mutations in all positive patients and we found that 13 out of 37 (35%) had type 1/type 1-like and 36 out of 37 (97%) with type 2/type 2-like. This CALR mutation profile in Egyptian patients appear different from the western status as type2/type 2-like is the highest in our patients (97%) versus 35-45% and type1/type 1-like was 35% versus 55-65% compared to western results. Meanwhile, the clinical course and phenotype of our cohort of patients is not similar to that in western as there is no significant difference of overall survival between type1/type1-like and type2/type2-like. This finding might be due to the different environmental and genetic backgrounds of Egyptian population. A part of it might be related to the HCV infection as 12 out of 37 (32%) had HCV infection. Further study is in progress on a large number of patients to correlate that with the clinicopathological status, response to therapy and the mechanistic pathway of oncogenic transformation. Disclosures No relevant conflicts of interest to declare.

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