Molecular Genetics of von Willebrand Disease in Korean Patients: Novel Variants and Limited Diagnostic Utility of Multiplex Ligation-Dependent Probe Amplification Analyses

BACKGROUND: von Willebrand disease (VWD), characterized by quantitative or qualitative defects of von Willebrand factor (VWF), is the most common inheritable bleeding disorder. Data regarding the genetic background of VWD in Korean patients is limited. To our knowledge, this is the first comprehensive molecular genetic investigation of Korean patients with VWD. METHODS: Twenty-two unrelated patients with VWD were recruited from August 2014 to December 2017 (age range 28 months–64 years; male:female ratio 1.2:1). Fifteen patients had type 1, six had type 2, and one had type 3 VWD. Blood samples were collected for coagulation analyses and molecular genetic analyses from each patient. Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed. In patients without sequence variants, multiplex ligation-dependent probe amplification (MLPA) was performed to detect dosage variants. We adapted the American College of Medical Genetics and Genomics guidelines for variant interpretation and considered variants of uncertain significance, likely pathogenic variants, and pathogenic variants as putative disease-causing variants. RESULTS: VWF variants were identified in 15 patients (68%): 14 patients with a single heterozygous variant and one patient with two heterozygous variants. The variants consisted of 13 missense variants, one small insertion, and one splicing variant. Four variants were novel: p.S764Efs*16, p.C889R, p.C1130Y, and p.W2193C. MLPA analysis in seven patients without reportable variants revealed no dosage variants. CONCLUSIONS: This study revealed the spectrum of VWF variants, including novel ones, and limited diagnostic utility of MLPA analyses in Korean patients with VWD.

Safety and Efficacy of B-domain Deleted Third Generation Recombinant Factor VIII (GreenGene F™) in Korean Patients with Hemophilia A: Data from a Post-marketing Surveillance Study

BACKGROUND: New B-domain deleted third generation recombinant factor VIII (FVIII; GreenGene F™, beroctocog alfa) was launched in 2010. We determined safety and efficacy of GreenGene F™ during routine clinical practice in patients with hemophilia A over a period of 12 months. METHODS: From July 2010 to July 2014, a total of 136 hemophilia A patients were enrolled in a post-marketing surveillance (PMS) study. Among them, 134 patients were assessed for drug safety and 114 patients were analyzed for drug efficacy. Patients with differing hemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. RESULTS: Among 134 patients evaluated, 85 (63.4%) had severe hemophilia. Ninety-two received a total of 1,266,077 units for prophylaxis, and 42 received 516,491 units for bleeding episodes. Three patients developed inhibitors. In 112 previously treated patients, one patient (0.9%) developed inhibitor after intensive FVIII treatment for surgery. Among 22 previously untreated patients, inhibitors were observed in 2 infants (9.1%). Overall, there were a total of 47 adverse events (other than inhibitors) of all types in 30 patients (22.4%), 11 in 10 patients (7.5%) of which were considered showing serious adverse events (SAEs); most of which were hemorrhages at different sites. None of the SAEs were judged as product related. An excellent/good efficacy rate of 91.3% for hemostasis and 89.4% for hemorrhage prevention was recorded. CONCLUSION: The results of this PMS study support the use of GreenGene F™ as safe and efficacious in hemorrhage prevention and treatment of hemophilia A. These results are consistent with the findings from previously published GreenGene F™ studies.

Clinical and Radiological Evaluation After Chemical Synovectomy With Rifampicin in Hemophilic Arthropathy: Korean Experience With a 2-Week Interval Protocol

OBJECTIVE: To assess the clinical outcome of chemical synovectomy with rifampicin in hemophilic arthropathy by using the World Federation of Hemophilia (WFH) scoring system and plain radiograph. METHODS: We performed rifampicin synovectomy (RS) on 30 joints of 28 hemophilic patients diagnosed as hemophilic arthropathy stage I–III (based on Fernandez-Palazzi clinical classification). Clinical status (bleeding frequency, pain, joint physical status) and radiological staging were evaluated as parts of the WFH scoring system before and 1 year after RS. The patients were divided into two groups by the Arnold-Hilgartner scale of the initial X-ray as stage 3 or less for the low-stage group (n=17) and over 3 for the high-stage group (n=13). RESULTS: Total WFH joint physical scores were reduced after injection, and the number of bleeding episodes and pain showed especially significant improvement. For other subscores of the WFH joint physical score, only swelling, range of motion, and crepitus showed statistically significant improvement. According to the severity of the radiologic finding, the WFH joint physical score of both the low-stage and high-stage groups showed significant improvement. In the radiological aspect, the low-stage group, without joint space narrowing at the initial plain radiograph, showed no further aggravation after injection. However, in the high-stage group, radiology found aggravation regardless of the procedure. CONCLUSION: It is suggested that chemical synovectomy with rifampicin may prevent hemarthrosis and improve clinical symptoms. Especially in the early stage of arthropathy without joint-space narrowing, it seems to have an additional benefit that delays radiological aggravation and preserves joint status.

The 2nd Meeting of National Control Laboratories for Vaccines and Biologicals in the Western Pacific

The Second Meeting of the National Control Laboratories for Vaccines and Biologicals in the Western Pacific, was jointly organized by the National Institute of Food and Drug Safety Evaluation of the Ministry of Food and Drug Safety in the Republic of Korea, and by the World Health Organization Regional Office for the Western Pacific. In the National Lot Release Systems session countries including Canada, China, Japan, Malaysia, Vietnam, and the Republic of Korea, all shared information on their current Lot Release Systems, including current practices and developments in risk-based official lot release of vaccines. In the session on Quality Control of Blood Products, experts from the National Institute for Biological Standards and Control shared quality control and research results for; blood coagulation factor VIII products, and the measurement of procoagulant activity in immunoglobulin products. Representatives from Japan proposed a regional collaborative study to test aggregated immunoglobulin free from complement activity. A cell-based Japanese encephalitis vaccine potency assay was proposed by representatives from Korea and they also called for voluntary participation of other National Control Laboratories in a collaborative study, on the first Korean Gloydius anti-venom standard. Participants agreed in general to continue communicating, and coordinate presentation of the study results.

Educational Interventions to Enhance Adherence to Prophylactic Treatment in Korean Hemophilia Patients / 임상소아혈액종양

BACKGROUND: A patient's adherence to prophylactic treatment is one of the most significant factors to achieve desired outcomes, in regards to the quality of life and treatment cost-effectiveness. The aim of this study is to evaluate the effectiveness of educational interventions in enhancing adherence to prophylactic treatment in Korean hemophilia patients. METHODS: The Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro) was used to measure adherence. The study design consisted of two groups. One group was not educated with the education card which presented the morning administration of clotting factor concentrates and self-infusion skill. The other group was educated with the card. The scores of each subscale in the two groups and scores focused on the ‘Timing’ subscale were compared. RESULTS: Participants were recruited from five hemophilia treatment centers in Korea with 95 eligible patients forming the uneducated group and 123 patients in the educated group. The mean total score was 40.4 and 39.9, respectively. The subscale mean scores of the uneducated group and educated group were 8.43 and 7.90 (Timing), 6.12 and 5.88 (Dosing), 6.43 and 6.33 (Planning), 5.99 and 6.35 (Remembering), 6.22 and 6.25 (Skipping), and 7.23 and 7.24 (Communicating), respectively. CONCLUSION: Results showed that education programs on prophylactic treatment for hemophilia patients need to be well-designed with precise and subject-appropriate contents. Although the mean total scores of VERITAS-Pro could not be improved, the appropriate timing of injection with the educational intervention was administered. Results suggest that this whole process can enhance Korean hemophilia patients' adherence to prophylactic treatment.

Global hemostatic assay of different target procoagulant activities of factor VIII and factor IX

BACKGROUND: Korean National Health Insurance reimburses factor VIII (FVIII) and factor IX (FIX) clotting factor concentrate (CFC) infusions to discrepant activity levels, allowing elevation of FVIII activity to 60 IU/dL and FIX to 40 IU/dL. We aimed to assess hemostatic response to these target levels using global hemostatic assays. METHODS: We enrolled 34 normal healthy men, 34 patients with hemophilia A, and 36 with hemophilia B, with residual factor activity of 3 IU/dL or less and without inhibitors. Patients with hemophilia A and B received injected CFCs according to reimbursement guidelines. Fifteen minutes after injection, we assessed hemostatic response with global hemostatic assays: thrombin generation assay (TGA), thromboelastography (TEG), and clot waveform analysis (CWA). RESULTS: Normal healthy men and patients with hemophilia A and B were 36.7, 37.2, and 35.1 years old, respectively. FVIII and recombinant FIX concentrate doses were 28.8 IU/kg and 43.6 IU/kg. Post-infusion FVIII activity rose from 0.5 IU/dL to 69.4 IU/dL, while FIX activity rose from 1.4 IU/dL to 46.8 IU/dL. Post-infusion peak thrombin concentrations in hemophilia A and B were 116.6 nM/L and 76.4 nM/L (P < 0.001). Post-infusion endogenous thrombin potential (ETP) in hemophilia A and B was 1349.8 nM/min and 915.6 nM (P < 0.001). TEG index of hemophilia A and B was 0.11 and −0.51 (P=0.006). CONCLUSION: Current reimbursed doses for FIX concentrates are insufficient to achieve hemostatic responses comparable to those after reimbursed doses for FVIII concentrates in terms of peak thrombin concentration, ETP, and TEG index.

A Multicenter Study on Korean von Willebrand Disease Realities / 임상소아혈액종양

BACKGROUND: von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of up to 1%. However in Korea, only 126 VWD patients were registered in Korea Hemophilia Foundation (KHF). The aim of this study was to determine the status of VWD patients in Korea. We analyzed VWD patients by age, gender, blood group, family history and bleeding history.METHODS: One hundred twenty-six VWD patients registered in the KHF by December 2016, and 74 patients diagnosed at six university hospitals were enrolled in this study. We evaluated the medical records from the KHF and the questionnaires from six university hospitals retrospectively.RESULTS: Seventeen patients misdiagnosed and ten patients duplicated were excluded. One hundred nine patients registered in the KHF and 64 patients diagnosed at six university hospitals met the criteria for VWD. The blood type O accounts for 72 (51.8%). VWF mutation was detected in 30 patients (17.3%). Median age at diagnosis was 10.5 yr. The bleeding score of adults was higher than that of children (P < 0.001). The most common bleeding symptom was epistaxis (48.5%). The distribution of VWD types was: 67% of type 1, 30.1% of type 2, and 2.9% of type 3.CONCLUSION: Even though only six hospitals responded to the survey, 64 patients not registered in the KHF were diagnosed with VWD. Our results suggest the prevalence of Korean VWD might be higher than previously reported. A nationwide registration system is warranted in order to accurately identify the national prevalence of VWD.

Direct Acting Antiviral Agents in Korean Patients with Chronic Hepatitis C and Hemophilia Who Are Treatment-Naïve or Treatment-Experienced

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. METHODS: Patients (n=30) were enrolled between September 2015 and April 2016. Twenty-six patients were genotype 1 (1b, n=21; 1a, n=5) and four patients were genotype 2a/2b. Among 21 patients with genotype 1b, Y93H resistance-associated variants (RAVs) were detected in three patients (14.3%). We evaluated sustained virologic response (SVRs) at 12 weeks, as well as relapse and safety. RESULTS: Five patients with genotype 1a and three patients with genotype 1b (RAV positive) received ledipasvir/sofosbuvir for 12 weeks. SVR12 rate was 100% (8/8). Eleven patients with genotype 1b were treatment-naïve and received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 91% (10/11). One patient experienced viral breakthrough without RAV at 12 weeks. Seven treatment-experienced patients with genotype 1b received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 85.7% (6/7). One patient experienced viral breakthrough with RAV (L31M, Y93H) at 12 weeks. Four patients with genotype 2a/2b received sofosbuvir plus ribavirin for 12 weeks. SVR12 rate was 100% (4/4). No serious adverse event-related discontinuations were noted. CONCLUSIONS: New direct acting antiviral treatment achieved high SVRs rates at 12 weeks in CHC patients with hemophilia without serious adverse events.

A Multicenter Study on Korean von Willebrand Disease Realities / 임상소아혈액종양

BACKGROUND: von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of up to 1%. However in Korea, only 126 VWD patients were registered in Korea Hemophilia Foundation (KHF). The aim of this study was to determine the status of VWD patients in Korea. We analyzed VWD patients by age, gender, blood group, family history and bleeding history. METHODS: One hundred twenty-six VWD patients registered in the KHF by December 2016, and 74 patients diagnosed at six university hospitals were enrolled in this study. We evaluated the medical records from the KHF and the questionnaires from six university hospitals retrospectively. RESULTS: Seventeen patients misdiagnosed and ten patients duplicated were excluded. One hundred nine patients registered in the KHF and 64 patients diagnosed at six university hospitals met the criteria for VWD. The blood type O accounts for 72 (51.8%). VWF mutation was detected in 30 patients (17.3%). Median age at diagnosis was 10.5 yr. The bleeding score of adults was higher than that of children (P < 0.001). The most common bleeding symptom was epistaxis (48.5%). The distribution of VWD types was: 67% of type 1, 30.1% of type 2, and 2.9% of type 3. CONCLUSION: Even though only six hospitals responded to the survey, 64 patients not registered in the KHF were diagnosed with VWD. Our results suggest the prevalence of Korean VWD might be higher than previously reported. A nationwide registration system is warranted in order to accurately identify the national prevalence of VWD.

Neonatal Hepatic Hemangioendothelioma: A Single Institute Experience / 임상소아혈액종양

BACKGROUND: Hepatic hemagioendothelioma in neonatal period was rarely seen, so standard treatment does not established yet.METHODS: A retrospective analysis of patients with neonatal hepatic hemangioendothelioma at Ajou University Hospital between 2001 and 2016 was performed.RESULTS: Six patients with hepatic hemangioendothelioma in neonatal period were founded. Mean age at diagnosis was 6.1 days (range, 1-26 days). Three patients have no symptoms; diagnostic approach was prenatal ultrasonography in 2 patients, and incidental abnormal ultrasonographic findings in 1 patient, but the other 3 patients have hepatomegaly and/or congestive heart failure. Three patients were observed without treatment and the other 3 patients received medical and/or surgical treatment. Three patients of those who did not receive treatment became spontaneous regression. Of the other 3 patients, 1 patient achieved complete tumor disappearance after surgical resection, another 1 patient achieved to decrease tumor size with interferon-alpha treatment for 6 months and then had complete resolution of tumor after partial liver lobectomy, and other 1 patient who received hepatic artery embolization decreased in the size and number of lesions and then regressed gradually.CONCLUSION: Asymptomatic patients with neonatal hepatic hemangioendothelioma could have spontaneous remission, but patients with symptoms such as hepatomegaly with congestive heart failure or thrombocytopenia needed to be applied with medical and/or surgical treatment.

Neonatal Hepatic Hemangioendothelioma: A Single Institute Experience / 임상소아혈액종양

BACKGROUND: Hepatic hemagioendothelioma in neonatal period was rarely seen, so standard treatment does not established yet. METHODS: A retrospective analysis of patients with neonatal hepatic hemangioendothelioma at Ajou University Hospital between 2001 and 2016 was performed. RESULTS: Six patients with hepatic hemangioendothelioma in neonatal period were founded. Mean age at diagnosis was 6.1 days (range, 1-26 days). Three patients have no symptoms; diagnostic approach was prenatal ultrasonography in 2 patients, and incidental abnormal ultrasonographic findings in 1 patient, but the other 3 patients have hepatomegaly and/or congestive heart failure. Three patients were observed without treatment and the other 3 patients received medical and/or surgical treatment. Three patients of those who did not receive treatment became spontaneous regression. Of the other 3 patients, 1 patient achieved complete tumor disappearance after surgical resection, another 1 patient achieved to decrease tumor size with interferon-alpha treatment for 6 months and then had complete resolution of tumor after partial liver lobectomy, and other 1 patient who received hepatic artery embolization decreased in the size and number of lesions and then regressed gradually. CONCLUSION: Asymptomatic patients with neonatal hepatic hemangioendothelioma could have spontaneous remission, but patients with symptoms such as hepatomegaly with congestive heart failure or thrombocytopenia needed to be applied with medical and/or surgical treatment.

Long-term course of anti-factor VIII antibody in patients with hemophilia A at a single center

BACKGROUND: Immune tolerance induction (ITI) can reduce inhibitors against factor VIII concentrates by 70-80%. In this study, we elucidated the characteristics of inhibitors and attempted to determine the proper indications and timing for ITI. METHODS: Subjects included hemophilia A patients registered at the Korea Hemophilia Foundation from 1991 through 2014. Inhibitors were classified as persistent and transient. Patients were classified into groups according to peak inhibitor titer: low (<2 BU/mL), moderate (2 to <5 BU/mL), high (5 to <10 BU/mL), and very high titer (≥10 BU/mL). RESULTS: Overall, 350 (21.4%) of 1,634 hemophilia A patients developed inhibitors at least once. Of these, 100 (6.1%) and 250 (15.3%) patients developed persistent and transient inhibitors, respectively. For transient inhibitors, the median peak titer was 1.0 BU/mL, persistent for median of 11.0 months (10.0, 8.0, 13.0, and 19.0 months in the low, moderate, high, and very high titer transient inhibitor groups, respectively). Overall, 95.8% (215), 72.2% (17), 52.4% (21), and 21.7% (97) of patients in the low, moderate, high, and very high titer groups became inhibitor-negative spontaneously, without ITI. CONCLUSION: Given the spontaneous disappearance of inhibitors and high cost of ITI, it is worthwhile to postpone ITI for 11 months unless the peak inhibitor titer is greater than 10 BU/mL.

The Benefit for Preoperative Coagulation Screening Test in Children / 임상소아혈액종양

BACKGROUND: We evaluated the value of preoperative screening for coagulopathy in children who have undergone elective surgery.METHODS: We retrospectively evaluated laboratory and bleeding histories in 39,884 patients aged greater than 1 year and lesser than 19 years who had undergone elective surgery from January 2003 to March 2015. All of the patients had preoperative coagulation screening with complete blood count, prothrombin time (PT) and activated partial thromboplastin time (aPTT). If PT and/or aPTT were abnormal, further studies, such as mixing test, coagulation factor assay, anti-phospholipid antibody studies were done.RESULTS: The study included 39,884 patients greater than 1 year and lesser than 19 years. Of 924 patients with prolonged PT and/or aPTT values, 63 were subsequently diagnosed with a factor deficiency.CONCLUSION: Our result suggests that preoperative coagulation screening tests have benefit when there are no histories of bleeding tendencies because timely diagnosis allows for proper treatment, as some hereditary factor deficiencies may escape clinical detection in asymptomatic patients. Routine preoperative coagulation screening may serve as a useful adjunct to clinical history.

Highly effective peginterferon alpha-2a plus ribavirin combination therapy for chronic hepatitis C in hemophilia in Korea

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. However, there are no published data on the efficacy of antiviral therapy in Korea. We assessed the safety and efficacy of combination therapy with peginterferon alpha-2a plus ribavirin for CHC in hemophilia. METHODS: Patients (n=115) were enrolled between March 2007 and December 2008. Seventy-seven patients were genotype 1 or 6, and 38 patients were genotype 2 or 3. We evaluated rapid virologic responses (RVRs), early virologic response (EVRs), end-of-treatment response (ETRs), sustained virologic response (SVRs), and relapses. Safety evaluations included adverse events and laboratory tests. RESULTS: Eleven patients were excluded from the study because they had been treated previously. Among the remaining 104 treatment-naive patients, RVR was achieved in 64 (60.6%), ETR was achieved in 95 (91.3%), and SVR was achieved in 89 (85.6%). Relapse occurred in eight patients (8.9%). Common adverse events were hair loss (56.7%) and headache (51.0%). Common hematologic adverse events were neutropenia (22.1%), anemia (27.9%), and thrombocytopenia (3.8%). However, there were no serious adverse events such as bleeding. RVR was the only predictor of SVR in multivariate analysis. CONCLUSIONS: Peginterferon alpha-2a plus ribavirin combination treatment produced a favorable response rate in CHC patients with hemophilia without serious adverse events.

The Benefit for Preoperative Coagulation Screening Test in Children / 임상소아혈액종양

BACKGROUND: We evaluated the value of preoperative screening for coagulopathy in children who have undergone elective surgery. METHODS: We retrospectively evaluated laboratory and bleeding histories in 39,884 patients aged greater than 1 year and lesser than 19 years who had undergone elective surgery from January 2003 to March 2015. All of the patients had preoperative coagulation screening with complete blood count, prothrombin time (PT) and activated partial thromboplastin time (aPTT). If PT and/or aPTT were abnormal, further studies, such as mixing test, coagulation factor assay, anti-phospholipid antibody studies were done. RESULTS: The study included 39,884 patients greater than 1 year and lesser than 19 years. Of 924 patients with prolonged PT and/or aPTT values, 63 were subsequently diagnosed with a factor deficiency. CONCLUSION: Our result suggests that preoperative coagulation screening tests have benefit when there are no histories of bleeding tendencies because timely diagnosis allows for proper treatment, as some hereditary factor deficiencies may escape clinical detection in asymptomatic patients. Routine preoperative coagulation screening may serve as a useful adjunct to clinical history.

Immune tolerance induction in patients with severe hemophilia A with inhibitors

BACKGROUND: Inhibitory antibodies to factor VIII (FVIII) are an important complication when managing patients with hemophilia A. Immune tolerance induction (ITI) has been regarded as a useful method for eradicating inhibitors. We report the results of a retrospective study in Korean patients with hemophilia A who underwent ITI. METHODS: We reviewed the records of patients with hemophilia A with inhibitors who underwent ITI from March 2004 to December 2014. ITI was started with FVIII concentrates at 100 IU/kg, 3 times per week. The dose of FVIII was reduced according to the inhibitor titer and recovery of FVIII. Inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. RESULTS: In total, 17 patients with severe hemophilia A were evaluated. Complete tolerance was achieved in 14 of 17 patients (83%). The mean peak inhibitor titer before ITI was 38.4 BU/mL. The mean treatment duration was 26.2 months. The mean duration between inhibitor detection and ITI was 5.1 years in the complete tolerance group and 10.8 years in the partial tolerance and failed group. CONCLUSION: This study shows that ITI can be an effective and well-tolerated method for eradicating inhibitors. Possible influencing factors for ITI success were age at the start of ITI treatment and duration after inhibitor detection. More research to provide further insight about other factors and conditions is needed.

Prevalence of Possible von Willebrand Disease / 임상소아혈액종양

BACKGROUND: Definition of possible von Willebrand disease (VWD) included levels of von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor activity (VWF:RCo) below 30 U/dL. The purpose of this study was to determine the prevalence of possible VWD in Ulsan, Korea. We also analyzed the influence of demographic factors such as age, gender, and blood group on subject levels of VWF.METHODS: Between March 2011 and September 2011 we prospectively investigated 1,039 subjects (271 children, 768 adults). Blood samples were collected for the determination of VWF:Ag, VWF:RCo, and factor VIII coagulation assay (FVIII:C). A standardized questionnaire was administered to evaluate hemorrhagic symptoms at the time of first examination, using a bleeding score ranging from 0 to 3.RESULTS: Forty five subjects met the criteria for possible VWD, for a prevalence of 4.3%. Subjects of Group O had a significantly lower mean FVIII:C, VWF:Ag, and VWF:RCo value than subjects of group A,B, or AB (P<0.001).CONCLUSION: Our results suggest that the prevalence of VWD may be much higher than previously reported. Efforts to increase the awareness and diagnosis of VWD may help improve identification of patients with bleeding disorders and lead to early, appropriate management with safe and efficacious therapies.

Prevalence of Possible von Willebrand Disease / 임상소아혈액종양

BACKGROUND: Definition of possible von Willebrand disease (VWD) included levels of von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor activity (VWF:RCo) below 30 U/dL. The purpose of this study was to determine the prevalence of possible VWD in Ulsan, Korea. We also analyzed the influence of demographic factors such as age, gender, and blood group on subject levels of VWF. METHODS: Between March 2011 and September 2011 we prospectively investigated 1,039 subjects (271 children, 768 adults). Blood samples were collected for the determination of VWF:Ag, VWF:RCo, and factor VIII coagulation assay (FVIII:C). A standardized questionnaire was administered to evaluate hemorrhagic symptoms at the time of first examination, using a bleeding score ranging from 0 to 3. RESULTS: Forty five subjects met the criteria for possible VWD, for a prevalence of 4.3%. Subjects of Group O had a significantly lower mean FVIII:C, VWF:Ag, and VWF:RCo value than subjects of group A,B, or AB (P<0.001). CONCLUSION: Our results suggest that the prevalence of VWD may be much higher than previously reported. Efforts to increase the awareness and diagnosis of VWD may help improve identification of patients with bleeding disorders and lead to early, appropriate management with safe and efficacious therapies.

THE STUDY OF MUTATION SPECTRUM OF HEMOPHILIA / Шинэ санаа Шинэ нээлт

Background:Hemophilia is life-threatening and hereditary bleeding disorder caused by deficiencies of pi coagulation VIII. IX, XI factor, and that is inherited by X-linkcd recessive.However, hemophilic treatment is getting increase in our country, but still insufficient or poor because of high cost, which is about 50000-70000$ per patient per year in other countries. Now, we need to detect hemophilia heterozygote (XAX*) or no symptomatic carrier among hemophiliac siblings (including mother, younger sister, sister) that is essential for prevention of hemophilia. We need to screen the mutation spectrum of FS and F9 gene among patients with hemophilia in order to detect hemophilia carriers.Objective:to detect a mutation 1'Ó ø! f9 gene among patients with hemophilia Methods:The blood samples were collected from paffeflf* who had been hospitalizing in department ot hematology of the First Clinical Hospital and the National Center for Maternal and Child Health from 2010 to 2011. We have carried out the screening of most common mutation named int- 22 inversion by Long-Range PC'R method is previously described by Lui Q et al.. 1998. Direct sequence method was used to detect the SNP and small deletion in patients who had no int-22 inv and large deletion.Results:In total, If pillitfhis with hemophilia (ÈË-14, IIB=1) participated in this study. The 9 patients positive for an int-22 inversion mutation, while the one patient had a multiple exon deletion (exon 1-13) which was demonstrated by repeated PC'R amplification failure. I wo missense mutation and 1 frame shift mutation were detected. The one patient had nonsense mutation but he was diagnosed as a severe hemophilia-A patient.Conclusion:We have to urgently adopt the molecular diagnosis and carrier detection ol hemophilia in our rnuntrv

THE STUDY OF MUTATION SPECTRUM OF HEMOPHILIA / Шинэ санаа Шинэ нээлт

Background: Hemophilia is life-threatening and hereditary bleeding disorder caused by deficiencies of pi coagulation VIII. IX, XI factor, and that is inherited by X-linkcd recessive. However, hemophilic treatment is getting increase in our country, but still insufficient or poor because of high cost, which is about 50000-70000$ per patient per year in other countries. Now, we need to detect hemophilia heterozygote (XAX*) or no symptomatic carrier among hemophiliac siblings (including mother, younger sister, sister) that is essential for prevention of hemophilia. We need to screen the mutation spectrum of FS and F9 gene among patients with hemophilia in order to detect hemophilia carriers. Objective: to detect a mutation 1'Ó ø! f9 gene among patients with hemophilia Methods: The blood samples were collected from paffeflf* who had been hospitalizing in department ot hematology of the First Clinical Hospital and the National Center for Maternal and Child Health from 2010 to 2011. We have carried out the screening of most common mutation named int- 22 inversion by Long-Range PC'R method is previously described by Lui Q et al.. 1998. Direct sequence method was used to detect the SNP and small deletion in patients who had no int-22 inv and large deletion. Results: In total, If pillitfhis with hemophilia (ÈË-14, IIB=1) participated in this study. The 9 patients positive for an int-22 inversion mutation, while the one patient had a multiple exon deletion (exon 1-13) which was demonstrated by repeated PC'R amplification failure. I wo missense mutation and 1 frame shift mutation were detected. The one patient had nonsense mutation but he was diagnosed as a severe hemophilia-A patient. Conclusion: We have to urgently adopt the molecular diagnosis and carrier detection ol hemophilia in our rnuntrv