Clinical manifestations and gene analysis of 18 cases of hereditary protein S deficiency / 中华血液学杂志

Objective: To analyze the clinical manifestations and molecular pathogenesis of 18 patients with inherited protein S (PS) deficiency. Methods: Eighteen patients with inherited PS deficiency who were admitted to the Institute of Hematology & Blood Diseases Hospital from June 2016 to February 2019 were analyzed: activity of protein C (PC) and antithrombin (AT) , PS activity were measured for phenotype diagnosis; high throughput sequencing (HTS) was used for screening of coagulation disease-related genes; Sanger sequencing was used to confirm candidate variants; Swiss-model was used for three-dimensional structure analysis. Results: The PS:C of 18 patients ranged from 12.5 to 48.2 U/dL. Among them, 16 cases developed deep vein thrombosis, including 2 cases each with mesenteric vein thrombosis and cerebral infarction, and 1 case each with pulmonary embolism and deep vein thrombosis during pregnancy. A total of 16 PROS1 gene mutations were detected, and 5 nonsense mutations (c.134_162del/p.Leu45*, c.847G>T/p.Glu283*, c.995_996delAT/p.Tyr332*, c.1359G> A/p.Trp453*, c.1474C>T/p.Gln492*) , 2 frameshift mutations (c.1460delG/p.Gla487Valfs*9 and c.1747_1750delAATC/p.Asn583Wfs*9) and 1 large fragment deletion (exon9 deletion) were reported for the first time. In addition, the PS:C of the deep vein thrombosis during pregnancy case was 55.2 U/dL carrying PROC gene c.565C>T/p.Arg189Trp mutation. Conclusion: The newly discovered gene mutations enriched the PROS1 gene mutation spectrum which associated with inherited PS deficiency.

Congenital factor X deficiency: a retrospective analysis of 11 cases / 中华血液学杂志

Objective: To analyze the clinical characteristics, laboratory examination, diagnosis, treatment, and outcome of hereditary factor Ⅹ (FⅩ) deficiency. Methods: Clinical data of 11 patients with congenital FⅩ deficiency were retrospectively analyzed from July 2009 to February 2021. Results: There were 3 males and 8 females. Median age was 39 (5-55) years. The media duration of follow-up was 81.67 (1.87-142.73) months. Of the 11 patients, 10 had bleeding symptoms, 7 had ecchymosis or hemorrhage after skin bump, 7 had nosebleed, 6 had gingival hemorrhage, and 1 had muscle hematoma. Among the female patients, 6 had menorrhagia and 1 experienced bleeding after vaginal delivery. Family history of FⅩ deficiency was found in one case. Eight patients had a history of surgery, and four had postoperative bleeding. Laboratory findings were characterized by significantly prolonged activated partial thromboplastin time, prothrombin time, and decreased FⅩ activity (FⅩ∶C) . Four cases underwent gene mutation analysis and five new mutations were found. Four cases were treated with prothrombin complex concentrates (PCC) and seven cases with fresh frozen plasma (FFP) . One female patient had significantly reduced menstrual volume after PCC prophylactic therapy. One patient received FFP for prophylactic infusion with no bleeding during and after the operation. Conclusion: Most patients with congenital FⅩ deficiency had bleeding symptoms and there was no significant correlation between severity of bleeding symptoms and FⅩ∶C. Prophylaxis should be applied in patients with severe bleeding tendencies. Gene mutation test is significant for screening, diagnosis, and prognosis prediction of congenital FX deficiency.

Clinical Analysis of Hospitalized Children with Primary Immune Thrombocytopenia / 中国实验血液学杂志

OBJECTIVE@#To investigate the factors affecting the chronicity of childhood primary immune thrombo-cytopenia (ITP) and compare the efficiency of different first-line treatment regimens.@*METHODS@#Children with ITP hospitalized in our hospital from September 2013 to October 2018 were retrospectively analyzed.@*RESULTS@#Three hundred and one children (150 males and 151 females) were included in this study, with a median age of 8 (0.17-17) years old, and 110 (36.5%), 92 (30.6%), and 99 (32.9%) cases were grouped into newly diagnosed, persistent, and chronic ITP, respectively. The median of follow-up was 41.92 (1.07-74.03) months. At the end of the follow-up (October 2019), among the 202 newly diagnosed/persistent ITP children, 79 cases (59 newly diagnosed and 20 persistent ITP) achieved remission within 1 year after initial diagnosis, with a remission rate of 39.3%; 122 cases (50 newly diagnosed and 72 persistent ITP) developed chronic disease, with a chronicity rate of 60.7%; one case underwent splenectomy. In 99 cases with chronic ITP, 5 cases underwent splenectomy. Multivariable logistic regression analysis showed that, the insidious onset of symptoms (OR=3.754, 95%CI: 1.882-7.488, P=0.000) increased the risk of chronicity, while the positive antibody to anti-platelet membrane glycoprotein (OR=0.446, 95%CI: 0.224-0.888, P=0.021) might reduce the risk of chronicity. And no difference was found by the analysis of subtype of anti-platelet membrane glycoprotein (P=0.305). The efficacy of the first-line treatment of intravenous immunoglobulin (IVIG) alone or combined with steroid was better than that of steroid alone (P=0.028, 0.028), however, the efficiency was not significantly different between IVIG alone and combined with steroid (P=0.086).@*CONCLUSION@#Insidious onset of symptoms in pediatric ITP increases the risk of chronicity, while the positive titer of anti-platelet membrane glycoprotein may reduce the risk. In the first-line treatment for the newly diagnosed/persistent children. The efficacy of IVIG alone or combined with steroid is better than that of steroid alone.

Clinical characteristics of 83 patients with thrombotic thrombocytopenic purpura / 中华血液学杂志

Objective: To analyze the clinical characteristics, treatment and prognosis of patients with thrombotic thrombocytopenic purpura (TTP) . Methods: 83 patients with TTP from May 1998 to May 2019 were analyzed retrospectively. Results: Among the 83 patients, there were 27 males and 56 females, with a median age of 39 (10-68) years. 41 cases (49.4%) showed pentalogy syndrome and 79 cases (95.2%) showed triad syndrome. 78.0% (46/59) of the patients had a PLASMIC score of 6 or higher. TTP gene mutations was detected in 5 of 10 patients. The activity of von Willebrand factor-cleaving protease (ADAMTS13) , which was detected in 10 patients before plasma exchange (PEX) , was less than 10% in 9 patients. 83 patients were treated with PEX/plasma infusion and glucocorticoid, 35 of which were treated combined with rituximab and/or immunosuppressant. The median follow-up was 34 (1-167) months, the effective rate was 81.9%, the remission rate was 63.9%, the relapse rate was (35.7 ±7.1) %, and the 3-year overall survival (OS) rate was (78.6 ±4.6) %. The effective rate (72.9%vs 94.3%, P=0.019) and OS rate[ (63.8±7.5) %vs (94.3±3.9) %, χ(2)=8.450, P=0.004] in the group treated with PEX/PI and glucocorticoid alone were lower than those in the group treated combined with rituximab and/or immunosuppressant. COX multivariate analysis showed that age (HR=1.111, 95%CI 1.044-1.184, P=0.001) and alanine transaminase (ALT) /aspartate aminotransferase (AST) (HR=1.353, 95%CI 1.072-1.708, P=0.011) were independent risk factors for OS. Conclusion: Most patients with TTP have triad syndrome, accompanied by a decrease in ADAMTS13 activity. Plasma infusion and glucocorticoid combined with rituximab, immunosuppressive therapy could improve overall survival. The prognosis of patients with older age and high ALT/AST ratio is poor.

Eltrombopag for the treatment of primary immune thrombocytopenia in 23 pediatric patients / 中华血液学杂志

Objective: To evaluate the efficacy and safety of eltrombopag in the treatment of pediatric primary immune thrombocytopenia (ITP) . Methods: The clinical characteristics of 23 pediatric ITP patients who received eltrombopag from May 2015 to March 2019 were retrospectively analyzed. Eltrombopag started with an initial dose of 12.5-50.0 mg/d and the maximum dose was 75.0 mg/d. Results: Among 23 children, there were 11 boys and 12 girls with median age 11.0 (2.0-17.0) years. Four cases were newly diagnosed ITP, the other 8 of persistent ITP and 11 of chronic ITP. The duration of eltrombopag application ranged from 4.5 to 95 weeks (8/23 still ongoing) . The median platelet (PLT) counts at 2 weeks, 4 weeks, 3 months and the 6 months after treatment were 40 (4-170) ×10(9)/L, 20 (4-130) ×10(9)/L, 60 (4-110) ×10(9)/L, and 70 (18-160) ×10(9)/L, which were all significantly higher than that before treatment 14 (2-82) ×10(9)/L (z=-3.440, P=0.001; z=-1.964, P=0.049; z=-4.339, P<0.001;z=-5.794, P<0.001 respectively) . The overall response rate was 60.87% (14/23 cases) . The median time to PLT count ≥30×10(9)/L was 10.5 (3-42) days. Seven patients (30.43%) responded within the first week, and 10 cases (43.48%) achieved PLT counts ≥30×10(9)/L within 2 weeks. All patients were divided into three groups according to the age (<6 years old, 6-12 years old, 13-17 years old) . The response rates were similar in three groups, as 33.33%, 60.00%, 85.71%, respectively. WHO bleeding scores as 0, 1, 2 were corresponded to 4, 12 and 7 patients before treatment. Patient numbers changed to 13, 7, 3 with bleeding scores 0, 1, 2 respectively after treatment (χ(2)=7.558, P=0.006) . Eltrombopag was well tolerated, the common adverse events included elevated transaminase (4 cases) and serum bilirubin (4 cases) ; mild nausea (1 case) , vomiting (1 case) and dizziness (1 case) . No drug withdrawal occurred due to adverse events. Conclusion: Eltrombopag is safe and effective in pediatric patients with primary ITP.

Symptomatic Profiles of 173 Chinese Patients with Essential Thrombocythemia / 中国实验血液学杂志

OBJECTIVE@#To explore the symptomatic burden of patients with essential thrombocythemia (ET) and its relation with clinical characteristics including the mutation status, therapeutic protocols and sex.@*METHODS@#Total of 173 Chinese ET patients were selected and grouped on the basis of disease characteristics (mutation status, therapeutic pro to- cols, and sex).@*RESULTS@#All the groups showed low-to-high symptom burden, with the highest in the Hu (hydroxyurea)-group (total symptom score [TSS], 14.7; range, 7.6-14.7). In the JAK2V617F-positive, Hu-treated, and female groups TSS and independent symptom scores were higher than those in the control group. The CALR-positive and IFN-α-treated groups had lower overall and individual scores as compared with groups lacking the corresponding characteristics. As the number of characteristics (JAK2V617F-positive, Hu-treated, and female) increases, the severity of symptoms gradually increased.@*CONCLUSION@#The different characteristics have various effects on symptom burden in ET patients. The accumulation of certain characteristics will lead to more severe symptom burden, thus the patient＇s symptom burden should be considered comprehensively when making up the treatment schemes and prognosis.

The incidence and risk factors for thrombosis in primary immune thrombocytopenia / 中华血液学杂志

Objective: To probe the incidence and risk factors for thrombosis in Chinese immune thrombocytopenia through a retrospective analysis of the inpatients referred to the Blood Disease Hospital, CAMS & PUMC. Methods: A retrospective survey of 3 225 patients with ITP from October 2005 to December 2017 was performed, the clinical data of the patients with thrombosis were collected to analyze the causes, diagnosis, treatment and prognosis. Results: A total of 46 patients experienced a thrombotic event with a prevalence of 1.43%(46/3 225 cases) with the median age of thrombosis as 54 years (26-83) years, the prevalence of thrombosis was 3.37% (40/1 187 cases) in>40 years old, which was significantly higher than 0.58% (6/1 030 cases) in those under 40 years old, in adults (P=0.00). There were 20 males and 26 females, there was no statistical difference in the incidence of thrombosis between males and females[1.53% (20/1 309) vs 1.36% (26/1 916), P=0.187]; The prevalence of arterial thrombosis was 1.12% (36/3 225) higher than venous thrombosis[0.22% (7/3 225), P=0.00]when 82.61%(38/46 cases) of patients with PLT<100×10(9)/L. Post-splenectomy are risk factors for thrombosis in ITP patients, P values was 0.022, There was no statistical difference in the presence or absence of thrombotic events whether received glucocorticoid or TPO/TPO-Ra treatment, the P values were 0.075 and 0.531, respectively. Conclusions: In Chinese population, ITP disease maybe with a higher risk of thrombosis, there was no positive correlation between thrombosis and platelet level; and had obvious age distribution characteristics. The history of tobacco, hypertension, diabetes and post-splenectomy are risk factors for thrombosis in ITP patients.

Clinical evaluation of Chinese disseminated intravascular coagulation scoring system (version 2017) in patients with acute promyelocytic leukemia / 中华血液学杂志

Objective: To evaluate the applicability of Chinese disseminated intravascular coagulation scoring system (CDSS) in the diagnose of DIC in patients with acute promyelocytic leukemia (APL) patients. Methods: Medical records of 220 APL patients diagnosed and receiving induction therapy in Blood Disease Hospital, CAMS & PUMC from January 2004 to February 2018 were retrospectively analyzed. Each patient was evaluated by CDSS, the International Society of Thrombosis and Haemostais (ISTH) scoring system for overt DIC and Japanese Ministry of Health and Welfare (JMHW) scoring system for overt DIC, respectively. Results: A total of 220 APL patients were enrolled in the study, with a median age of 38.5 (12-70) years, 114 male and 106 female. Among them, 173 were in the low-medium risk group, 47 high-risk group; 11 patients died during induction treatment. The positive rates of DIC diagnosed by CDSS criteria, ISHT criteria, JMHW criteria was 62.27%, 54.09%, 69.09%, respectively. The consistency rate of CDSS and ISTH in diagnosing DIC was 78.10%; the consistency rate of CDSS and JMHW was 88.32%. There was significant difference in PT, APTT, FIB, D-Dimer and FDP in DIC(+) and DIC(-) group by CDSS (all P<0.05), but patients in the DIC(+) group had lower level of D-Dimer than in the DIC(-) group [21.9(1.2-477.1) mg/L vs 26.3(0.6-488.7) mg/L, χ(2)=1.871, P=0.002] by ISTH, and there was not significant difference in APTT by JMHW [27.05(18.0-181.0) s vs 26.15(18.2-35.5) s, χ(2)=1.162, P=0.134]. In this study, both of the gender and age had no difference in the DIC (+) and DIC (-) group by CDSS. Univariate analysis showed that the level of WBC and the percent of abnormal promyelocytic cells in bone marrow when diagnosed were different in DIC (+) and DIC (-) group by CDSS (P<0.05). Multiple analysis showed the level of WBC (OR=3.525, 95% CI 1.875-6.629, P<0.001) was the only independent predictor in DIC diagnosis by CDSS. Conclusion: The sensitivity of diagnosing DIC by CDSS was higher than the ISTH; and the specificity was superior to JMHW. Using CDSS can help to make the DIC diagnosis and treatment in time for APL patients who with the coagulation abnormalities.

A phase Ⅲ multi-center clinical trial on safety and efficacy of a domestic plasma derived factor Ⅸ for the treatment of patients with hemophilia B / 中华血液学杂志

Objective: To evaluate the efficacy and safety of a domestic human plasma derived coagulation Factor Ⅸ concentrate (pd-FⅨ) in patients with hemophilia B. Methods: The study was a multicenter, open-label and single-arm study. The efficacy of pd-F Ⅸ was evaluated by objective performance criteria. The doses of pd-FⅨ were calculated according to the bleeding symptom and disease severity. The infusion efficiency of pd-FⅨ and improvement of bleeding symptoms were measured at 30 minutes and (24±4) h after the first infusion, respectively. Adverse events were recorded. Viral infection and FⅨ inhibitor were detected 90 d after the first infusion. Results: All 36 subjects with hemophilia B were enrolled in the study. The median age of these patients was 31 years old and the median injection doses were 4 (1-17) times. The hemostatic effect of 27/36 (75.00%) and 9/36 (25.00%) acute bleeding events were rated as "excellent" and "better" , respectively. The recovery rate was 111.92% (65.55%-194.28%) at 30 minutes after infusion of FⅨ. There was no adverse event related to FⅨ. No reactivation of HBV, HCV or HIV and FⅨ inhibitor was detected at 90-104 d after the first FⅨ infusion. Conclusion: This domestically made human plasma derived FⅨ concentrate is safe and effective in the treatment of acute bleeding in patients with hemophilia B. Clinical trial registration: China food and Durg Administration, 2016L08027.

The efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia / 中华血液学杂志

Objective: To investigate the safety and efficacy of eltrombopag for adult patients with chronic immune thrombocytopenia (cITP). Methods: It was a randomised, single-centre, 6 weeks, placebo-controlled study. Beginning in January 29(th), 2013, 35 patients were enrolled, and the trial was completed on May 16(th), 2014. 17 patients were assigned to receive eltrombopag (starting dose 25 mg/d) and 18 were assigned to receive placebo. Results: A total of 35 cases of adult cITP, 6 males and 29 females with a median age of 42(22-66) years were enrolled. One patient withdrew from eltrombopag treatment group for the adverse event (AE) and discontinued treatment. In first two weeks, 27.78% (5/18) of placebo-treated compared with 64.71%(11/17) of eltrombopag-treated patients achieved platelet counts ≥ 30×10(9)/L(P=0.031); Treatment 6 weeks, the proportion of platelet counts reached ≥50×10(9)/L and ≥ 30×10(9)/L in eltrombopag-treated were higher than placebo-treated ones with statistically significant differences in both groups [64.71%(11/17) vs 11.11% (2/18), P=0.001; 76.47% (13/17) vs 38.89% (7/18), P=0.028]; The study also indicated a statistically significant difference in favour of eltrombopag compared with placebo in the odds of achieving the outcome of a platelet count ≥ 50×10(9)/L at least once during 6-week treatment (94.11% vs 33.33%, P<0.001), and 70.59%(12/17) of patients with the platelet count continuously ≥ 50×10(9)/L in 50% of treatment time in eltrombopag-treated group was more than placebo-treated one [11.11%(2/18), P<0.001]. Proportions of patients who required rescue treatment were 44.44% in placebo group and none in eltrombopag-treated one, respectively (P=0.002); The odds of bleeding symptoms with the WHO bleeding scale had no difference in both groups after 6 weeks (P=0.066). Adverse events that occurred more frequently due to eltrombopag than placebo included increased transaminase (3/17) and blood bilirubin (5/17), cerebral infarction(1/17). Conclusions: The thrombopoietin receptor agonist eltrombopag was a suitable therapeutic option for Chinese adults with cITP.

Clinical Characteristic of "triple-negative" Essential Thrombocythaemia Patients and Mutation Analysis by Targeted Sequencing / 中国实验血液学杂志

<p><b>BACKGROUND</b>Essential thrombocythemia is a subgroup of myeloproliferative neoplasms. Previous studies identified mutations of JAK2, CALR, and MPL that are closely related with the pathogenesis of myeloproliferative neoplasms. All these mutations contribute to the hyperactivation of JAK2/STAT pathway. However, a small proportion of essential thrombocythemia patients does not display such mutations. The pathogenesis of "triple-negative" form of essential thrombocythemia remains unknown.</p><p><b>OBJECTIVE</b>To investigate the clinical characteristics of triple-negative essential thrombocythemia and related mutation genes.</p><p><b>METHODS</b>To identify the mutations associated with triple-negative essential thrombocythemia, next-generation sequencing was used to conduct targeted sequencing of 360 genes in samples from 68 patients.</p><p><b>RESULTS</b>At least one missense mutation was detected in all the patients and all the detected genes. After screening the data, it was observed that 10 genes with the 10 highest mutation were follows: FLT3, SH2B3, ASXL1, ADAMTS1, TET2, TP53, EGFR, CUX1, GATA2, and MPL.When only rare genes (i.e., with a frequency in Asian populations lower than 5%, as estimated by the 1000 Genomes Project) were analyzed, the most frequently mutated genes in the patients were TET2 (33.82%), SH2B3(29.41%), and ASXL1 (23.53%). Our study identified some mutations that did not previously reported. Although all these mutations need further validation, high incidence rates may indicate relevance of the respective mutations to essential thrombocythemia pathogenesis. Some of the detected mutations have been previously reported; these mutations were also found in a large proportion of our subjects.</p><p><b>CONCLUSION</b>whole-exon sequencing can provide a higher level of accuracy for gene mutation analysis and assist in identifying mutations that contribute to illustrate the pathogenesis of essential thrombocythemia.</p>

Clinical Characteristics and Long-Term Outcome of 125 Chinese Young Patients with Essential Thrombocythemia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the clinical characteristics and long-term outcome of Chinese young patients (≤40 years) with essential thrombocythemia(ET), and to develop a thrombosis predicting model specific for young patients with ET, so as to provide a new evidence for risk stratification and treatment.</p><p><b>METHODS</b>Medical records of 125 Chinese young patients with newly diagnosed of ET were retrospectively analyzed.</p><p><b>RESULTS</b>The median age at diagnosis was 32 (18-40) years old, with 37 males and 88 females. During follow-up, 18 patients (14.4%) experienced major thrombotic events. JAK2 V617F (HR=8.895, P=0.001), history of thrombosis (HR=8.001, P<0.001) and WBC≥12.0×10/L (HR=5.225, P=0.002) were independent risk factors for thrombosis. The incidence of thrombosis and risk factors in young patients were different from that in general ET population, so a thrombosis predicting model specific for young patients with ET was developed. In this model, JAK2 V617F (score 2), history of thrombosis (score 2) and WBC≥12.0×10/L (score 1) were used to divide the patients into low risk (score 0), intermediate risk (score 1-2) and high risk (score≥3) groups. These 3 groups exhibited significantly different thrombosis-free survival (χ=32.223, P<0.001). Antiplatelet treatment could prevent the occurrence of thrombosis (HR=0.081, P<0.001), while cytoreductive agents significantly decreased the risk of thrombosis only in intermediate and high risk groups (14.3% vs 36.4%, χ=4.416, P=0.036). Seven patients (5.6%) evolved to myelofibrosis, and one of them finally progressed in to acute leukemia. The only risk factor for evolution was WBC≥15.0×10/L (χ=5.434, P=0.020). Neither antiplatelet treatment nor cytoreductive agents could prevent disease progression.</p><p><b>CONCLUSION</b>The incidence of thrombosis and risk factors in young patients with ET are different from that in general ET population. The thrombosis-predicting model specific for young patients with ET is useful for guiding therapeutic decisions.</p>

Role of Toll-like receptor 2 in primary immune thrombocytopenia / 中国实验血液学杂志

The aim of this study was to explore the role of Toll-like receptor (TLR) 2 in primary immune thrombocytopenia (ITP) by detecting TLR2 expression in the peripheral blood lymphocytes of patients with ITP and evaluating the role of TLR2 activation on inflammatory cytokine secretion. A total of 39 ITP patients and 21 normal controls were enrolled in this study. The expression of TLR2 was detected by real-time PCR and flow cytometry, and the concentration of IL-6 and TNF-α in culture supernatant of PBMNC treated with pam3CSK4 for 48 hours were detected by ELISA. The results showed that the expression of TLR2 mRNA in active ITP patients (3.561 ± 0.741) was significantly higher than that in normal controls (1.750 ± 0.314) (P < 0.05), but there was no statistically significant difference between remission ITP patients (2.333 ± 0.448) and normal controls (P > 0.05) . Flow cytometry analysis found that the TLR2 was not expressed on T and B cells, but expressed on all monocytes both from ITP patients and normal controls. Further activation experiment showed that TLR2 activation in vitro could induce the expression of IL-6 (1644 ± 634.0 vs 4111 ± 525.2 pg/ml) and TNF-α (75.37 ± 22.31 vs 326.0 ± 109.9 pg/ml) in PBMNC from ITP patients (both P < 0.05), but just could promote IL-6 expression in normal controls (2119 ± 636.9 vs 4671 ± 315.9 pg/ml)(P < 0.05). It is concluded that the expression of TLR2 mRNA is up-regulated in PBMNC of ITP patients, and this increased TLR2 maybe participate in ITP through inducing secretion of inflammatory cytokines.

Clinical characteristics of 520 children with hemophilia in a single medical center / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the clinical characteristics, diagnosis and treatment of pediatric hemophilia in single center over the decade.</p><p><b>METHODS</b>A retrospective study was conducted with 520 hemophilic children hospitalized in our medical center between January 2002 and December 2012.</p><p><b>RESULTS</b>All the patients were male including 438 hemophilia A (HA) and 82 hemophilia B (HB). There were significant differences in APTT between severe and mild- to moderate hemophilia (P<0.05). In pediatric HA and HB, delay time of diagnosis were 1.42 and 1.17 year, respectively. Children of 7-12 years were the largest population of visiting a doctor, and the spontaneous bleeding episode was the main cause. The most common hemorrhage site was soft tissue in early childhood, but joint was increasingly affected with age as children growth. All bleeding sites and frequencies were not associated with plasma factor level of patient (P>0.05). Knee and anKle were mainly involved in early child, while elbow and shoulder were involved increasingly in later childhood. Additionally, in HA and HB, inhibitor occurrence were 8.9%(19/214) and 12.8%(5/39), inducing 78.9%(15/19) and 40.0%(2/5) of high titer inhalator, and antiHCV-positive rate were 2.8%(11/397) and 2.5%(2/79), respectively.</p><p><b>CONCLUSION</b>Our data highlights that delay in diagnosis and blood-borne infections were significantly reduced over the decade, but the development of inhibitor still remains a major challenge with wide-scale usage of factor in replacement therapy.</p>