Clinical observation of desmopressin in the treatment of 15 patients with DDAVP / 中华血液学杂志

Objective@#To assess the significance of DDAVP use in the diagnosis and treatment of VWD.@*Methods@#An analysis of 15 VWD cases who referred to Hematology Division of First affiliated Hospital of Soochow University and treated with DDAVP from March 2016 to August 2018 was conducted. Efficacy and treatment response of DDAVP were monitored by observations of changes in factor Ⅷ procoagulant (FⅧ∶C) and von Willebrand Factor (VWF) related indicators before and 2 h after DDAVP injection.@*Results@#Of 15 cases with VWD, 7 males and 8 females with a median age of 23 (6-46) years, 7 of 9 type I VWD patients achieved complete response (CR) , 1 type 2A VWD case CR, 5 type 3 VWD ones no response (NR) . The VWF multimer analysis in 5 patients combined with other plasma VWF values were in accordance with the known diagnosis.@*Conclusions@#DDAVP was effective in most type 1 patients, and ineffective in some type 2 and almost all type 3 cases. It was helpful for diagnosis and subsequent treatment planning.

The diagnostic value of PLASMIC score in the discrimination between thrombotic thrombocytopenic purpura and disseminated intravascular coagulation / 中华血液学杂志

Objective@#PLASMIC score was evaluated its value in differential diagnosis between the patients with thrombotic thrombocytopenic purpura (TTP) and those with disseminated intravascular coagulation (DIC) .@*Method@#Twenty-four patients with TTP and 41 cases with DIC were retrospectively analyzed in this study. The platelet count, average red blood cell volume, indirect bilirubin, creatinine and prothrombin time international normalised ratio were collected, and then PLASMIC scores were calculated.@*Results@#According to the risk classification of PLASMIC score, three (12.5%) TTP patients had moderate risk, and the rest 21 (87.5%) cases had high risk. In DIC patients, 92.7% cases were in low risk group, 4.9% at moderate risk, and only one case had high risk. Of these 65 patients, the sensitivity and the specificity to TTP of the high risk of the scoring system were 87.5% and 97.6%, respectively.@*Conclusion@#The patients with high risk of PLASMIC score correlated well with clinical TTP diagnosis. The scoring system showed to be an excellent diagnostic model to distinguish TTP patients from those with DIC.

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.

α1-antitrypsin Pittsburg mutations: report of two cases in the same family / 中华血液学杂志

Objective@#To analyze the clinical and laboratory abnormalities of two patients with α1-antitrypsin (α1-AT) Pittsburgh in a family and review the literatures.@*Methods@#Both plasma clotting time and factor activities were performed using clotting or substrate methods. Platelet aggregation was evaluated using an optical aggregometer. The serum protein electrophoresis was performed on Sebia HYDRASYS by using Agarose gel. The exons of α1-AT were amplified by using polymerase chain reaction (PCR) and then sequenced and compared with NCBI GenBank records.@*Results@#The proband had several ruptures of corpus luteum and bleeding after operation, while her daughter had no bleeding history. Both of them showed prolonged coagulation tests which could not be corrected by mixing with the normal plasma. They also showed low levels of plasma coagulation factors, undetected protein C and S activity and abnormal bands of α1-globulin. The results of gene sequencing demonstrated that they were heterozygous for g.T17132G (p.Met358Arg) mutation of α1-antitrypsin gene (NG_008290.1) .@*Conclusions@#Comparing with the data of previously reported cases, our results confirmed the obvious abnormality of coagulation test and the discrepancy of bleeding tendency of α1-antitrypsin Pittsburgh patients, and suggested that the rupture of corpus luteum would be a specific characteristic in women of child-bearing age.

Detection and analysis of plasma VWF levels in healthy Chinese by automatic standardized assay / 中华血液学杂志

Objective@#To explore the normal range of plasma VWF levels of healthy Chinese and to analyze the influencing factors to VWF level.@*Methods@#To detect the levels of von Willebrand factor antigen (VWF∶Ag) , von Willebrand factor ristocetin cofactor activity (VWF∶Rco) , von Willebrand factor collagen binding activity (VWF∶CB) , and the factor Ⅷ coagulation activity (FⅧ∶C) by using fully automatic and standardized testing instruments and matching reagent in 70 healthy Chinese. The effects of age, ABO blood type, gender and region were also analyzed. Meanwhile, 8 standard plasma samples (2 normal subjects, 6 cases of type 2 VWD) confirmed by NIBSC were tested for VWF values.@*Results@#① In 70 cases of healthy Chinese, the mean value of plasma VWF∶Ag, VWF∶Rco and VWF∶CB were (95.4±44.9) %, (105.9±35.4) % and (89.8±28.4) %, respectively; the ratio of VWF∶Rco/VWF∶Ag and VWF∶CB/VWF∶Ag was 1.18±0.25 and 1.03±0.29, respectively. ②There was no statistical significance in plasma VWF values between the age ≥30 years and <30 years group (P>0.05) . ③The VWF∶Rco, VWF∶CB of type O blood group were lower than that of non-O group (t=2.074, P=0.042; t=3.949, P=0.001) , but there was no statistical significance in VWF∶Ag, VWF∶Rco/VWF∶Ag, VWF∶CB/VWF∶Ag between the two groups (P>0.05) . ④There was no significant difference in VWF values between male and female groups (P>0.05) . ⑤The VWF∶Ag, VWF∶CB of the northern population (North area of Huaihe River) group were higher than that of southern population (Suzhou area) group (t=4.525, P=0.001; t=3.214, P=0.002) , but VWF∶Rco/VWF∶Ag, VWF∶CB/VWF∶Ag were lower than that of southern population group (t=6.373, P=0.001; t=2.902, P=0.005) , and there was no significant difference in VWF∶Rco between the two groups (t=1.598, P=0.115) . ⑥The VWF values of 8 standard plasma samples were in accordance with the known diagnosis.@*Conclusions@#A more integrate plasma VWF levels of healthy Chinese people were obtained for the first time by using fully automatic and standardized testing instruments. It was also found that ABO blood group and region had a significant impact on the level of VWF, while the age and gender had no significant effect.

A single-center clinical study of 22 patients with acquired hemophilia / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the feature of underlying disorders, clinical symptoms, diagnosis and treatment strategies of patients with acquired hemophilia(AH).</p><p><b>METHODS</b>The clinical data and laboratory tests results of 22 patients with AH from March 2010 to June 2014 were retrospectively analyzed.</p><p><b>RESULTS</b>A total of 22 patients with AH were enrolled in our study, including 20 patients diagnosed as acquired hemophilia A (AHA) and 2 as acquired hemophilia B (AHB). Among the AHA patients, there were 10 males and 10 females with the median age of 37.5 (range, 2-95) years old. The median activity of FVIII (FVIII:C) of the 20 AHA patients was 1.9% (0.5%-39.0%). Soft tissue hematoma (80.0%) and subcutaneous bleeding (75.0%) were the most common clinical symptoms. Two male children were diagnosed as AHB (age 1 and 3 years old, respectively) with mild bleeding symptoms, and the activities of FIX (FIX:C) were 5.0% and 16.0%, respectively. In addition, an underlying disorder was found in 7 patients (31.8%). In laboratory testing, all patients had prolonged APTT, normal PT, decreased FVIII:C or FIX:C, positive antibody screening test or antibody titer (2-32 BU), and negative for lupus anticoagulant and anticardiolipin antibody. Nineteen out of 20 patients were treated with blood products to stop acute bleeding episodes. Corticosteroid alone was applied to 7 patients, corticosteroid combined with other immunosuppressive agents to 11 patients, rituximab to 3 patients. Nineteen patients responded well to hemostatic treatment, except 1 patient who died of fatal bleeding. The FVIII:C of 8 patients increased to a normal level with the median time of 42.5(21-145) days. After treatment, the activity of FIX:C of the 2 AHB patients achieved 35% and 24% in 48 and 60 days, respectively.</p><p><b>CONCLUSION</b>Acquired hemophilia is not an uncommon disease in clinical practices, which can occur in people of all ages. AH is a bleeding disorder with heterogeneous characteristics. Compared with adult, the clinical symptoms of children patients were mild, which lead to underdiagnosis.</p>

Hypofibrinogenemia caused by long-term administration of hemocoagulase: three cases report and literature review / 中华血液学杂志

<p><b>OBJECTIVE</b>A first report of 3 patients who developed hypofibrinogenemia due to long-term administration of hemocoagulase.</p><p><b>METHODS</b>The clinical data of three patients with hypofibrinogenemia due to long-term administration of hemocoagulase were analyzed, and the related literature was reviewed.</p><p><b>RESULTS</b>Case 1, a two-year old girl, had liver traumatic rupture and then treated with massive transfusion and fibrinogen infusion in addition to intravenous recombinant factor VIIa (two times) and hemocoagulase (2 U/d). The liver wound bleeding was soon stopped. However, her plasma fibrinogen level decreased to 0.12 g/L after continuous administration of hemocoagulase for 18 days. Case 2, a three-year old boy, had liver traumatic rupture and was treated with surgical repair, and then received hemocoagulase (2 U/d). On the 8th day, a large amount of blood was found to exude from abdominal cavity drainage tube and indwelling venous catheter, and his fibrinogen dropped to 0.24 g/L. Case 3 was a 45 year-old man who underwent a total mandibular resection because of malignant tumor, and he was given hemocoagulase (4 U/d). A continuous blood oozing was noted from his operation incision, and his fibrinogen level decreased to 0.25 g/L. All the three patients'plasma fibrinogen levels and coagulation tests returned to normal ranges after discontinuation of hemocoagulase administration and supplement of fibrinogen, and the bleeding stopped in cases 2 and 3.</p><p><b>CONCLUSION</b>Long-term use of hemocoagulase could induce hypofibrinogenemia and severe bleeding.</p>

The clinical studies of 51 patients with thrombotic thrombocytopenic purpura / 中华血液学杂志

<p><b>OBJECTIVE</b>To comprehensively analyze the clinical characteristics, treatment strategies and outcome of patients with thrombotic thrombocytopenic purpura (TTP).</p><p><b>METHODS</b>A retrospective survey of 51 TTP patients confirmed in our database. Relevant statistical analyzes were performed by GraphPad Prism 5 software.</p><p><b>RESULTS</b>51 cases of patients with acquired TTP were identified as idiopathic TTP. In our study, only 18 cases (35.29%) had typical pentalogy of TTP, where thrombocytopenia (100.00%), microangiopathic hemolytic anemia (92.16%) and neurologic abnormalities (88.24%) were more common than fever (72.55%) and renal abnormalities (70.59%). Plasma ADAMTS13 activity was detected in 37 patients with TTP with ADAMTS13 deficiency confirmed in 31 patients (83.78%). Plasma exchange with response of 72.3% was still the preferred strategy in TTP with individuation. Among 36 survival TTP patients, 8 patients (22.22%) relapsed. 15 patients (29.41%) died in our study. The mean ages of responders and deaths were of (37.5±14.5) and (50.1±18.9) respectively; whereas total bilirubin level of responders and deaths were of (43.3±23.5)μmol/L and (63.7±39.7) μmol/L respectively, the differences were statistically significant. Conversely, body temperature, WBC, HGB, PLT, serum creatinine and LDH showed no significant differences (P>0.05).</p><p><b>CONCLUSION</b>The diagnosis of TTP was based on comprehensive analysis of clinical manifestations. Plasma ADAMTS13 activity test had a higher clinical practical value. The therapeutic alliance with corticosteroids, immunosuppressive agents and Rituximab significantly improved its outcome. The age and high total bilirubin level at onset were associated with less sensitive to plasmapheresis and poor prognosis.</p>

Clinical studies of 162 patients with von Willebrand disease / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyse the epidemiological feature, clinical characters and therapeutic regimens for von Willebrand disease(VWD).</p><p><b>METHODS</b>The clinical data and laboratory tests results of 162 VWD patients in our center were analyzed.</p><p><b>RESULTS</b>There were 76 males and 86 female among these patients with the mean age of 7.2(2.0-41.0) and 20.7(5.0-48.0) years, respectively. 86 patients (53.1%) were identified to be type 1 VWD, 34 patients (21.0%) type 3 VWD and 42 patients (25.9%) type 2 VWD. Among type 2 VWD patients, 33 patients were type 2A, 4 patients type 2M, 5 patients type 2B. Eighty-seven patients (53.7%) had a definite family history of bleeding tendency. The most common and specific bleeding symptoms were easy bruising (61.7%), epistaxis (53.7%), prolonged bleeding after surgery or minor injury (53.1%). Menorrhagia (66.3%) was common in female patients. The analysis of Vicenza bleeding scores in all patients showed that only 56(34.6%) patients had abnormal bleeding scores. FVIII/VWF concentrates and cryoprecipitate were applied to 45 patients (27.8% ), Desmopressin (DDAVP) to 8 patients. Eight female patients need oral contraceptives jointly to control menorrhagia. Hysterectomy had to be performed in 2 female patients with VWD.</p><p><b>CONCLUSION</b>VWD was a common congenital bleeding disorder with heterogeneous characters, it was necessary to screen, identify, classify accurately this disease in order to supply to effectively individualized treatment.</p>

The diagnostic value of protein induced by vitamin K absence or antagonist-ii in non-infant patients with acquired deficiency of vitamin K-dependent coagulation factors / 中华内科杂志

Objective To explore the diagnostic value of protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) in non-infant with acquired deficiency of vitamin K-dependent coagulation factors (ADVKCF).Methods PIVKA-Ⅱ levels were measured by ELISA in 50 patients with ADVKCF on day 0,3,7 after vitamin K treatment.Prothrombin time(PT),APTT,FⅡ ∶ C,FⅦ∶ C,FⅨ∶ C,and FⅩ∶ C were analyzed simultaneously.Twenty healthy subjects were enrolled as controls.Results The average level of PIVKA-Ⅱ in ADVKCF group was (3.83 ± 1.40) μg/L,while (1.30 ± 0.54) μg/L in the control group (P ＜ 0.05).The PIVKA-Ⅱ levels on day 0 and 3 did not show significant difference [(3.83 ± 1.40) μg/Lvs (3.79 ± 0.66) μg/L,P ＞ 0.05],but decreasing significantly on day 7 compared to the control group (P ＜ 0.05).The PIVKA-Ⅱ level was (3.78 ± 1.30) μg/L in patients receiving plasma transfusion,while (3.91 ± 1.49)μg/L in no-plasma-transfusion group (P ＞ 0.05).Coagulation factors Ⅱ,Ⅶ,Ⅸ and Ⅹ activity which decreased significantly before treatment returned to normal range after one week use of vitamin K,leading to complete correction of prolonged APTT and PT (＞ 100 seconds).Conclusions The PIVKAⅡ level in ADVKCF patients is significantly higher than that of healthy subjects within one week treatment of vitamin K,which is not influenced by plasma transfusion.This study suggests that PIVKA-Ⅱ is a more sensitive parameter than APTT,PT and the activity of coagulation factor,which could be a valuable factor in the early diagnosis of ADVKCF.

Analysis of the cinical features and misdiagnosis in 62 patients with acquired deficiency of vitamin Kdependent coagulation factors / 中国综合临床

Objective To explore the clinical features and causes of misdiagnosis of the patients with acquired deficiency of vitamin K-dependent coagulation factors (ADVKDCF). Methods Retrospective analysis was performed with the data from 62 patients with ADVKDCF for etiological factors, clinical manifestations,laboratory examinations, diagnosis and treatments. Results Among the 62 patients, 51 patients were with unknown causes( subgroup A) and 11 were with clear histories of anticoagulant rodenticide poisoning( subgroup B). The presentations of hemorrhage of the patients varied with hematuria as the most common first symptom,followed by skin, mucosa, muscle, internal organs bleeding (28/62). The most common hemorrhage symptom is hematuria. 35 of the 62 patients had hemoglobin(Hb) levels less than 100 g/L due to blood loss( the lowest level was 32 g/L). Thirty-eight patients were misdiagnosed at the first visit and the median time from hemorrhage manifestation to definite diagnosis was 8 days (range,2 to 192 days). ADVKDCF was mostly misdiagnosed as the urinary system diseases (23/38), followed by hemophilia (8/38). Laboratory examinations showed normal platelet count , throm bin time (TT) and normal fibrinogen(Fg) concentration, but prolonged plasma prothrombin time (PT), activated partial prothrombin time (APTT) and international normalized ration (INR). All of patients received high dose vitamin K ( intravenous vitamin K1 with a initial dose of 20 to 240 mg/d and then oral vitamin K4 maintenance) . The bleeding symptoms disappeared 1 day after treatment and the Hb levels increased dramatically. There were significant differences in PT, APTT and INR of the patients before and after treatment( P ＜0. 01 ). Followed by a median follow - up of 8 months , no patient had severe adverse effects or recurrence. Conclusion The hemorrhage presentations of the patients with ADVKDCF are various. The most common hemorrhage symptom is hematuria. The misdiagnosis rate of ADVKDCF is high with urinary systems disorders as the most common misdiagnosis. Sequential treatment with vitamin K is an effective and safe method to prevent recurrence. Early detection of coagulation function is helpful to reduce misdiagnosis possibility.

Measurement of alloantibodies against FⅧ in patients with hemophilia A using a newly-developed ELISA and its clinical application / 中华检验医学杂志

Objective An ELISA-based assay for detecting alloantibodies against FⅧ was established to estimate the incidence of alloantibodies against FⅧ in treated patients with hemophilia A. Methods One hundred and forty patients with hemophilia A and 80 healthy controls were enrolled. Among hemophilia A patients, 84, 34 and 22 patients were in severe, moderate and mild conditions respectively. All patients were treated with plasma-derived FⅧ concentrates before. The titer wells were coated with MoAb against FⅧ which was developed in our laboratory. Then human recombinant FⅧ concentrates were applied. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti-human IgG were added successively. Finally Absorbance (A490) were measured and recorded. Inhibitor activity against FⅧ for all plasma samples was measured by a modified Nijmegen assay simultaneously. Results The results showed that alloantibodies against FⅧ were found in 40.0% (56/140) patients by ELISA. And the alloantibody incidences in the severe and non-severe patients were 47.6% (40/84) and 28.5% (16/56)respectively. There was statistical significance between these two categories (x2 = 5.079, P ＜ 0.05 ). The FⅧ inhibitor activity was detected in 24.3% (34/140) patients by modified Nijmegen assay. The inhibitor incidences in the severe and non-severe patients were 33.3% (28/84) and 10.7% (6/56) respectively.There was statistical significance (x2 = 9.349, P ＜ 0.05). Twenty-five patients were positive for FⅧ alloantibodies by ELISA but had no FⅧ inhibitor activity by the modified Nijmegen assay. The positive rates of FⅧ alloantibodies and inhibitor activity were 40.0% (56/140) and 24.3% (34/140) respectively,which had significant difference (x2 = 15.75, P ＜ 0.01 ) and strong positive correlation ( rn = 0.59, P ＜0.01 ). Meanwhile the results deduced from these two tests shared a high consistency rate ( Kappa = 0.55,P ＜0.01 ). Conclusions The detection rate for alloantibodies against F Ⅷ is enhanced by our newlydeveloped ELISA. Our results suggest that the occurrence of the alloantibodies against F Ⅷ in Chinese hemophilia A patients is not rare and the alloantibody incidence is preponderant in the patients with severe hemophilia A compared with non-severe hemophilia A patients.