Objective:To analyze the clinical manifestation, laboratory examination, treatment and prognosis of congenital factor Ⅺ (FⅪ) deficiency.Methods:The clinical data of 80 patients with congenital FⅪ deficiency in our hospital from September 2006 to October 2020 were analyzed retrospectively.Results:Among the 80 patients, there were 33 males (41.3%) and 47 females (58.8%) , with a median age of 32 (2-66) years. Twenty-eight cases (35.0%) had bleeding events, including 11 cases of spontaneous bleeding (13.8%) , 9 cases of ecchymosis or bleeding after skin trauma (11.3%) , 9 cases of postoperative bleeding (11.3%) . Among the female patients, there were 11 cases of menorrhagia (23.4%) and 1 case of bleeding after vaginal delivery (2.1%) . Laboratory examination were characterized by prolonged activated partial thromboplastin time (APTT) , normal prothrombin time (PT) , and decreased FⅪ activity (FⅪ∶C) . Nine patients (11.3%) were tested for FⅪ gene (F11) with 11 mutations. Twenty-seven patients (33.8%) received fresh frozen plasma (FFP) treatment, 15 patients (18.8%) were received for prophylaxis with no bleeding occurred during and after operation.Conclusion:Most patients with congenital FⅪ deficiency have no or mild bleeding symptoms. There was no significant correlation between FⅪ∶C and the severity of bleeding symptoms, and there was a well consistency between FⅪ∶C and F11 homozygous or heterozygous mutation type. Prophylactic infusion of FFP can effectively reduce the risk of operative bleeding.

Objective:To analyze the clinical phenotype and molecular pathogenesis of nine patients with hereditary factor Ⅴ (FⅤ) deficiency.Methods:Nine patients with hereditary FⅤ deficiency who were admitted to the Institute of Hematology and Blood Diseases Hospital from April 1999 to September 2019 were analyzed. The activated partial thromboplastin time, prothrombin time, and FⅤ procoagulant activity (FⅤ∶C) were measured for phenotypic diagnosis. High-throughput sequencing was employed for the F5 gene mutation screening, Sanger sequencing was adopted to confirm candidate variants and parental carrying status, Swiss-model was used for three-dimensional structure analysis, and ClustalX v.2.1 was used for homologous analysis.Results:The FⅤ∶C of the nine patients ranged from 0.1 to 10.6. Among them, eight had a hemorrhage history, with kin/mucosal bleeding as the most common symptom (three cases, 37.5%) , whereas one case had no bleeding symptom. There were five homozygotes and four compound heterozygotes. A total of 12 pathogenic or likely pathogenic mutations were detected, of which c.6100C>A/p.Pro2034Thr, c.6575T>C/p.Phe2192Ser, c.1600_1601delinsTG/p. Gln534*, c.4713C>A/p.Tyr1571*, and c.952+5G>C were reported for the first time.Conclusion:The newly discovered gene mutations enriched the F5 gene mutation spectrum associated with hereditary FⅤ deficiency. High-throughput sequencing could be an effective method to detect F5 gene mutations.

Objective:To investigate the clinical type and gene mutations, clinical manifestations, laboratory tests, diagnosis, and fibrinogen replacement therapy of congenital fibrinogen disorders.Methods:Clinical data of 146 patients with congenital fibrinogen disorders diagnosed from April 2000 to November 2020 were retrospectively analyzed.Results:Among the 146 patients, 61 (41.8%) men and 85 (58.2%) women had a median age of 33.5 years at the time of consultation. 34 patients (34.7%) were found to suffer from the disease due to bleeding symptoms, 33 patients (33.7%) due to preoperative examination. 55 patients (56.1%) had at least one bleeding symptom, and 42 patients (42.9%) had no bleeding symptoms. There is a negative correlation between fibrinogen activity concentration and bleeding ISTH-BAT score (rs=-0.412, P=0.001) . A total of 34 gene mutations were detected in 56 patients, of which 84.1% were missense mutations, and 16 new mutations were found. FGA Exon2 and FGG Exon8 mutations accounted for 71.4% of all mutation sites. Patients with afibrinogenemia were younger, with a median age of 2 (1-12) years, an ISTH-BAT score of 4, and patients with dysfibrinogenemia had significantly longer thrombin time (TT) , with a median of 28.5 (19.2-36.6) s. The 1 hour in vivo recovery (IVR) after fibrinogen infusion was (127.19±44.03) %, and the 24 hour IVR was (101.78±43.98) %. In addition to the obvious increase in the concentration of fibrinogen activity, the TT and the prothrombin time (PT) both decreased significantly, and the TT decreased more significantly, with an average decrease of 15.2% compared to the baseline after 24 hours of infusion. Conclusion:Most patients with congenital fibrinogen disorders have mild or no bleeding symptoms. Patients with afibrinogenemia have more severe symptoms. There is a negative correlation between the fibrinogen and the degree of bleeding. Genetic testing is helpful for the diagnosis of disease classification. FIB∶C/FIB∶Ag<0.7 can be used as a basis for clinical diagnosis. The TT can be used as the basis for the diagnosis of dysfibrinogenemia and the effectiveness of fibrinogen infusion.

Objective:To improve the understanding of splenectomy for treating common variable immunodeficiency complicated with cytopenia.Methods:A case of common variable immunodeficiency complicated with cytopenia was reported, and the literature was reviewed.Results:The patient, female, 16 years old, was hospitalized for eight years due to thrombocytopenia; she manifested recurrent thrombocytopenia with leukopenia since adolescence. The patient was diagnosed with common variable immunodeficiency with repeated mild infections, splenomegaly, and significantly reduced plasma immunoglobulin levels. Additionally, splenectomy was performed with adequate immunoglobulin replacement therapy, and the pathology confirmed hypersplenism; her blood cell level returned to normal after surgery.Conclusions:Common variable immunodeficiency has various clinical manifestations and can be complicated with cytopenia. Under the premise of adequate immunoglobulin replacement therapy, splenectomy is a safe and effective treatment for common variable immunodeficiency in patients with recurrent cytopenia.

Objective:To explore the pathogenesis, clinical characteristics, laboratory findings, diagnosis, treatment, and prognosis of congenital factor Ⅶ (FⅦ) deficiency.Methods:Clinical data of 43 patients with congenital FⅦ deficiency diagnosed from April 1999 to September 2019 were retrospectively analyzed.Results:There were 27 females and 16 males. Median age was 16 (1-70) years. Family history was found in 6 cases. There were 29 (67.4%) cases with bleeding symptoms, most common of which were mucocutaneous bleeding (13 cases, 30.2%) , oral bleeding (13 cases, 30.2%) , and epistaxis (9 cases, 20.9%) . Menorrhagia occurred in 11 cases (47.6% of female patients who were in fertile age) . Laboratory findings were characterized by significantly prolonged prothrombin time (PT) , normal partial thromboplastin time (APTT) , and decreased FⅦ activity (FⅦ∶C) . Ten cases received gene mutation analysis and 3 new mutations were found. Fourteen cases (32.6%) were treated with prothrombin complex concentrates (PCC) , 12 (27.9%) with fresh frozen plasma (FFP) , and 3 (7.0%) with human recombinant activated FⅦ (rFⅦa) . Twenty cases (46.5%) with no or mild bleeding symptoms did not receive any replacement therapy. Previous bleeding symptoms recurred in 5 patients (11.6%) , 8 females still had heavy menstrual bleeding, and 9 patients (20.9%) were lost to follow-up.Conclusion:Most patients with congenital FⅦ deficiency have mild or no bleeding symptoms, but have a tendency to excessive bleeding after surgery or trauma. There is no significant correlation between FⅦ∶C and severity of bleeding symptoms. Prophylaxis should be applied in patients with severe bleeding symptoms and rFⅦa is the first choice. Gene mutation test is significant for screening, diagnosis, and prognosis prediction of the disease.

Objective: To analyze the gene mutation spectrum, clinical features, and the factors of disease progression and prognosis in patients with essential thrombocytosis (ET) . Methods: A retrospective analysis was conducted on 178 newly diagnosed ET patients admitted from February 1st, 2009 to November 1st, 2018. Results: Of the 178 patients, 89 were male and 89 female, and the median diagnosis age was 49.5 (3-86) years old. JAK2V617F, CALR and MPL mutations frequencies were 16.45% (1.67%-43.90%) , 40.00% (10.00%-49.15%) and 25.10% (25.00%-40.00%) , respectively. Compared with patients with CALR mutations, patients with JAK2V617F mutation had higher diagnosis age (P=0.035) , higher white blood cell count (P=0.040) , higher hemoglobin concentration (P=0.001) , and lower platelet count (P=0.002) , respectively. Of them, 47 patients (27.01%) developed thrombotic events before diagnosis, and 3 ones (1.72%) experienced thrombotic events after diagnosis. Multivariate analysis revealed age >60 years (P=0.013, OR=4.595, 95%CI 1.382-15.282) and cardiovascular risk factors (CVF) (P<0.001, OR=8.873, 95%CI 2.921-26.955) as risk factors for thrombotic events, CALR mutation (P=0.032, OR=0.126, 95%CI 0.019-0.838) as a protective factor for thrombotic events. Age >60 years (P=0.042, OR=4.045, 95%CI 1.053-15.534) was found to be a risk factor for the overall survival (OS) of ET patients. OS of age ≤60 years and age>60 years were calculated by Kaplan-Meier analysis to be (115.231±1.899) months and (83.291±4.991) months (χ²=6.406, P=0.011) , respectively. Conclusion Age>60 years and CVF were risk factors for thrombotic event. CALR mutation was a protective factor for thrombotic event. Age >60 years was a risk factor for OS in ET patients.

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) ×10⁹/L, 20 (4-130) ×10⁹/L, 60 (4-110) ×10⁹/L, and 70 (18-160) ×10⁹/L, which were all significantly higher than that before treatment 14 (2-82) ×10⁹/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 ≥30×10⁹/L was 10.5 (3-42) days. Seven patients (30.43%) responded within the first week, and 10 cases (43.48%) achieved PLT counts ≥30×10⁹/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 (χ²=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.

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 ≥ 30×10⁹/L(P=0.031); Treatment 6 weeks, the proportion of platelet counts reached ≥50×10⁹/L and ≥ 30×10⁹/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 ≥ 50×10⁹/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 ≥ 50×10⁹/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.

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, χ²=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, χ²=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.

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<100×10⁹/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.