Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome

Thrombocytopenia absent radii (TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5′ untranslated region (5′UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5′UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5′UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP‐dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome.     

Danazol for the treatment of thrombocytopenia in patients with myelodysplastic syndrome

Thrombocytopenia is a poor prognostic indicator in the myelodysplastic syndromes (MDS). Treatment options for patients with symptomatic thrombocytopenia are limited. Danazol, an attenuated androgen, may have some efficacy in increasing the platelet count of patients with MDS. We retrospectively reviewed 33 patients with primary MDS who were treated with danazol for 6 or more weeks. After 6 weeks on danazol, the mean platelet count increased from 42 x 10(9)/L to 60 x 10(9)/L (P < 0.015), and 25 out of 33 patients (76%) had an increase in their platelet counts. Following 12 weeks of treatment, the mean platelet count increased to 67 x 10(9)/L (P < 0.005), and 21 out of 29 patients (72%) had an increase in their platelet counts. Seven out of nine patients no longer required platelet transfusions because bleeding stopped after 6 weeks on danazol. Mean duration of response was 10 months (range 2-68 months). Responses were seen in all French-American-British (FAB) subtypes and in all International Prognostic Scoring System (IPSS) scores. Therapy was well tolerated. Danazol may be effective in MDS patients who are thrombocytopenic.     

Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies

Immune thrombocytopenia purpura (ITP) is characterized by destruction of circulating platelets and the presence of antiplatelet antibodies. Many of the current immunomodulatory therapies act by reducing platelet destruction and usually do not have a lasting effect. This prospective, exploratory study characterized patients with ITP by identifying their demographic and comorbid clinical factors, use of treatments, serologic markers of autoimmunity, and possible relationships between platelet counts, concentrations of endogenous thrombopoietin (eTPO), and the presence of circulating anti-TPO antibodies. Data including medical history and laboratory evaluations were collected at a single patient visit on 205 patients (19 children, 186 adults). Reported histories revealed a 5% rate of thrombotic/ischemic events. Autoimmune markers including direct antiglobulin test and antinuclear antibodies were found more frequently than in the normal population; antiplatelet antibody testing was not done. eTPO concentrations were comparable to concentrations found in healthy volunteers. Our study confirmed that no significant inverse correlation occurred between circulating concentrations of eTPO and platelet counts in patients with ITP (Spearman r = -0.15). Two of the 205 patients tested (1%) had neutralizing activity of recombinant human TPO in a biological assay; however, this activity was confirmed to be anti-TPO antibody in only 1 patient.     

济南市近10年来发热伴血小板减少综合征流行特征及时空聚集性分析北大核心CSCD

目的通过分析济南市近10年来发热伴血小板减少综合征病例的三间分布及时空聚集性,为科学防控我市发热伴血小板减少综合征提供依据。方法病例资料来源国家疾病监测信息报告管理系统,采用描述性流行病学方法对济南市近10年来的流行病学特征进行分析,同时采用时空重排扫描统计方法分析其时空分布特征。结果济南市首例病例报告时间为2010年;近10年来累计报告病例数462例,死亡57例,平均病死率12.34%;病例发病集中在4-10月,8月为发病高峰;发病年龄在14~89岁,平均年龄为(63.11±11.36)岁,职业分布以农民为主,占89.83%;男女性别比为1.59∶1;济南市历城区、长清区和章丘区是报告病例数的主要高发地区,占病例总数的79.87%;时空聚集性分析结果提示全市共探测到13个时空聚集区,具有显著时空聚集性。结论济南市发热伴血小板减少综合征以历城区、长清区和章丘区为高发地区,8月为发病高峰月;该病存在时空聚集性,应针对农民等高发人群、主要高发地区开展病例监测、健康宣教等防控措施。     

发热伴血小板减少综合征病例中无形体病鉴别诊断与治疗

目的 确定发热伴血小板减少综合征患者中是否存在人粒细胞无形体病(human granulocytic anaplasmosis,HGA),并进行HGA临床分析.方法 将2010年收治的42例发热伴血小板减少综合征患者血液标本,送中国疾病预防控制中心(Centers for Disease Control and Pre...     

浙江省天台县发热伴血小板减少综合征流行特征及隐性感染状况调查

目的了解浙江省天台县发热伴血小板减少综合征发病特点及流行特征。方法采用主动监测和病例流行病学调查,采集监测对象及病例血清学标本,用荧光定量PCR方法进行检测;以描述性流行病学的方法对2012-2015年天台县发热伴血小板减少综合征病例及相关监测数据进行分析。结果 2012-2015年,天台县共报告发热伴血小板减少综合征病例12例,死亡2例;其中男性5例,女性7例;发病最小年龄39岁,最大年龄75岁;发病高峰在4-8月份;蜱虫叮咬史有8例(67%)。临床表现主要为发热(100%)、畏寒和乏力(83%)、全身酸痛(75%);重点地区无症状人群新型布尼亚病毒核酸监测阳性率1.4%。结论天台县已发现多例发热伴血小板减少综合征病例,而且从无症状人群中检测到新型布尼亚病毒核酸,应加强发热伴血小板减少综合征病例监测、防控及健康教育工作。     

Mutational screening of thrombopoietin receptor gene (c-mpl) in patients with congenital thrombocytopenia and absent radii (TAR)

Thrombocytopenia with absent radii (TAR) is a rare autosomal recessive disease characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia. We performed mutational screening of coding and promoter regions of the c-mpl gene, encoding thrombopoietin (TPO) receptor, by sequence analysis in four unrelated patients affected by TAR syndrome. Our results indicate that c-mpl gene mutations are not a common cause of thrombocytopenia in TAR syndrome.     

不同抗血小板治疗方案对急性冠状动脉综合征合并基线血小板中度减少患者预后的影响

目的:探讨不同抗血小板治疗方案对急性冠状动脉综合征(ACS)合并基线血小板中度减少(mTP)患者的再发心肌梗死及出血事件的影响.方法:回顾性入选2017年8月—2019年11月于郑州大学第一附属医院住院的ACS合并基线mTP患者418例,根据不同抗血小板方案分为单抗组和双抗组.收集入选患者临床基线资料,采用倾向性评分匹...     

山东省发热伴血小板减少综合征时空流行特征分析

目的 分析山东省发热伴血小板减少综合征(SFTS)的时空分布特征,为查找重点区域及聚集时间,采取针对性的干预措施,优化卫生资源配置提供科学依据。方法 基于2010-2016年山东省各县(市、区)网络报告的SFTS疫情数据,结合人口数据、地理数据,建立地理信息数据库,采用Open GeoDa 1.2.0软件进行空间自相关分析,采用SaTScan 9.4软件进行时空扫描聚类分析。结果 2010-2016年山东省累计报告SFTS病例2 319例,平均发病率为0.34/10万,累计报告死亡病例230例,平均病死率9.92%,发病数和发病率逐年增多。全局自相关分析显示,2012-2016年SFTS空间分布均具有自相关性,呈聚集性分布, Moran’s I值均为正值(P<0.05);局部自相关分析结果表明,高-高流行区主要位于淄博、泰安、莱芜、威海、烟台等市的相关县区。时空扫描分析发现3个时空聚集区域:1)2012年1月至2015年1月,以烟台市芝罘区为中心点,共覆盖16个县(市、区)(LLR=677.15,RR=11.58,P<0.001)。2)2013年1月至2016年12月,以泰安市新泰市为中心点,共覆盖6个县(市、区)(LLR=457.51,RR=9.25,P<0.001)。3) 2013年1月至2014年1月,以潍坊市安丘市为中心点,共覆盖28个县(市、区)(LLR=142.59, RR=4.97,P<0.001)。结论 山东省发热伴血小板减少综合征疫情分布存在明显的时空聚集特征,主要集中在泰安、莱芜、烟台、威海的相关县(市、区),是我省预防控制该病的重点区域。     

Aggregometry in the settings of thrombocytopenia,thrombocytosis and antiplatelet therapy

A variety of laboratory tests have been developed, which can diagnose a number of both congenital and acquired disorders of platelet function. Many tests of platelet function measure the ability of platelets to adhere to each other, forming platelet aggregates, which represent the major constituents of hemostatic plugs and of arterial thrombi. Light transmission aggregometry (LTA) is still considered the gold standard of platelet aggregation tests, but other platelet aggregation-based tests are also available. Among them, the flow cytometry-based methods may be more convenient than LTA for the study of patients with very low or very high platelet counts. The use of platelet aggregation tests has also been advocated to monitor the treatment with antiplatelet agents (mostly the P2Y₁₂ antagonist clopidogrel) of patients with thrombotic arterial occlusions, with the aim of improving their efficacy and safety. However, randomized clinical trials failed to show any advantage of this strategy; as a consequence, international guidelines now recommend against laboratory monitoring of antiplatelet therapy.     

Heparin-induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases

Heparin-induced thrombocytopenia and/or thrombosis (HITT) are serious complications of heparin treatment. The incidence, as previously reported, varies widely and, in consequence, is not precisely known. Moreover, most reports only concern clinically defined heparin-induced thrombocytopenia. Therefore we carried out a prospective study of the incidence of serologically confirmed HITT.
All patients admitted to the Departments of Cardiology and Neurology of our institution with an indication for treatment with therapeutic-dose intravenous unfractionated heparin were enrolled in the study. The patients were examined daily for the occurrence of thromboembolic complications. Regular platelet counts and tests for the presence of heparin-dependent antibodies were carried out using two different tests: a quantitative platelet factor 4/heparin (PF4/hep) Elisa, and a functional test, the heparin-induced platelet activation assay (HIPAA). HITT was defined as a rapidly occurring (within 5 d) decrease of the platelet count from normal values of >120 ×10⁹ l to <60 ×10⁹ l or to <100 ×10⁹ l if there was a rapid fall of >50% of starting value or >30% with concomitant acute thrombosis.
The observed incidence of HITT was 1/358 patients (0.3%, 95% confidence limits 0.01–1.5%). However, Elisa PF4/hep specific IgG antibodes were demonstrated in nine (2.5%) and IgM antibodies in seven (2.0%) of 358 patients. 30/358 patients (8.4%) had platelet activating antibodies in the HIPAA.
We conclude that the incidence of serologically confirmed HITT in this study is very low (0.3%) in patients with cardiac and neurologic diseases treated with intravenous unfractionated heparin. The frequency of heparin-dependent antibodies without concomitant occurrence of thrombocytopenia is much higher.     

Hereditary types of thrombocytopenia with giant platelets and inclusion bodies in the leukocytes

Summary Three forms of hereditary thrombocytopenia with giant platelets and inclusion bodies in the leukocytes have thus far been recognized. The May-Hegglin anomaly is characterized by giant platelets and spindle-shaped inclusion bodies in the leukocytes, which consist of 7–10 nm parallel-lying filaments. The Fechtner syndrome is a variant of the Alport syndrome, with inclusion bodies consisting of dispersed filaments, ribosomes and a few segments of rough and smooth endoplasmic reticulum. The Sebastian platelet syndrome shows the same platelet and leukocyte morphology observed in the Fechtner syndrome, but the additional anomalies e.g., the Alport syndrome, are lacking. The clinical signs and symptoms are variable. Most patients show only a mild bleeding tendency or are asymptomatic, but cases of severe postoperative hemorrhage have also been reported. Platelets can vary greatly in number, but are usually in the range of 20,000 to 120,000 platelets/µl, showing a mean platelet volume of 15–20 fl, unimpaired in vitro function and, in addition to their size and unorganized microtubular system, normal morphology. To date, no platelet membrane defects have been defined. Because the megakaryocyte number and platelet kinetics are normal, the pathogenesis of thrombocytopenia in these giant platelet syndromes is unresolved; this is also true of the leukocyte inclusion bodies. Because of the ubiquity of electronic particle counters, asymptomatic patients are increasingly being identified, but they are often misdiagnosed as having autoimmune thrombocytopenia.     

Heparin-induced thrombocytopenia with thrombosis: Incidence,analysis of risk factors,and clinical outcomes in 108 consecutive patients treated at a single institution

Heparin-induced thrombocytopenia with thrombosis (HITT) can lead to serious morbidity and may be potentially fatal. We reviewed our experience with this entity over a 4-year period, to determine the following: 1) incidence and type of thrombosis in patients with heparin-induced thrombocytopenia (HIT), 2) clinical consequences of thrombosis, i.e., amputation, cerebrovascular accidents and death, 3) risk factors associated with development of thrombosis, and 4) impact of therapy on clinical outcomes in patients with HITT. Between 1991–1994, 108 patients were diagnosed to have HIT by heparin-induced platelet aggregation test. Thirty-two (29%) of these developed thrombotic complications, of which 20 were venous, 8 arterial, and 4 both. Five of the 32 died, 3 underwent amputations, and 3 had cerebrovascular accidents. The patients who developed thrombotic complications, when compared to those with HIT alone, were older (68.7 ± 11.5 vs. 63.3 ± 16 years, P = .05), had more severe thrombocytopenia (platelet count 46,300 ± 30,400/mm³ vs. 62,500 ± 34,400/mm³, P = .02), and developed it earlier (6.0 ± 2.9 vs. 7.4 ± 3.1 days, P = .03). Multivariate analysis showed that severity of thrombocytopenia and early fall in platelet count were independent risk factors for development of thrombotic complications. We did not find an association between development of thrombosis and clinical events (myocardial infarction, cardiac procedures or surgery, noncardiac surgery, and sepsis) that occurred immediately prior to onset of thrombocytopenia. Heparin was stopped in all 32 patients with HITT. Six received no additional therapy, and one received a single dose of aspirin. Three of these 7 died. The other 25 received anticoagulant or multiagent therapy, with 2 deaths. The death rate was lower in those who were treated with anticoagulant or multiagent therapy (P = .05). We conclude that: 1) Thrombotic complications occur in about 29% of hospitalized patients who develop HIT. 2) Early, severe fall in platelet count in elderly patients receiving heparin appears to be associated with development of thrombotic complications. 3) Our data do not show an association between development of thrombotic complications and clinical events immediately preceding the diagnosis of HIT. 4) In addition to discontinuation of heparin, anticoagulant or thrombolytic therapy should be considered in patients with HITT. Am. J. Hematol. 56:12–16, 1997. © 1997 Wiley-Liss, Inc.     

一起聚集性发热伴血小板减少综合征病原S基因分子进化分析

目的 对2020年4月南京鼓楼医院送检的一起疑似聚集性发热伴血小板减少综合征(SFTS)开展病原检测,对其S基因进行测序,分析基因分型和系统发育特征。方法 采用荧光定量PCR法对6例疑似患者血清标本进行新型布尼亚病毒(SFTSV)核酸定性检测, RT-PCR扩增SFTSV S基因片段并测序。分析核苷酸同源性,构建系统进化树。结果 6例血清样本中,SFTSV核酸阳性5例。5例核苷酸高度同源,其中4例S片段基因核苷酸序列同源性100%,1例与其他4例间同源性为99.7%;最大相似株为江苏2014年分离株JS2014-06、2015年分离株JS2015-26,同源性100%。5例均聚集在C2亚型分支上。结论 聚集性疫情SFTSV基因型为C2型,与近年来国内分离株亲缘关系近。需加强监测和宣教,关注病毒的进化与变异。     

Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw–Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients

Upshaw–Schulman syndrome (USS) is a congenital thrombotic thrombocytopenic purpura (TTP) due to mutations in the gene that encodes for ADAMTS13 ( ADAMTS13 ), but its clinical signs may be mild or absent during childhood. We have identified 37 patients with USS (24 females, 13 males) belonging to 32 families. The nine women from six families who were diagnosed during their first pregnancy are the focus of this report. Six of the nine women had episodes of thrombocytopenia during childhood misdiagnosed as idiopathic thrombocytopenic purpura. Thrombocytopenia occurred during the second–third trimesters in each of their 15 pregnancies, with 16 babies (one twin pregnancy), often followed by TTP. Of 15 pregnancies, eight babies were stillborn or died soon after birth, and the remaining seven were all premature except one, who was born naturally following plasma infusions to the mother that had started at 8 weeks' gestation. All nine USS women had severely deficient ADAMTS13 activity. ADAMTS13 analyses demonstrated that eight women were compound heterozygotes of Y304C/G525D (2 siblings), R125VfsX6/Q1302X (2 siblings), R193W/R349C (2 siblings), I178T/Q929X, and R193W/A606P; one woman was homozygous for R193W. Only the R193W mutation has been previously reported. These observations emphasize the importance of measuring ADAMTS13 activity in the evaluation of thrombocytopenia during childhood and pregnancy.     

Mutations of the WASP gene in 10 Japanese patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, immunodeficiency, and eczema. X-linked thrombocytopenia (XLT) is a mild form of WAS with isolated thrombocytopenia. Both phenotypes are caused by mutation of the Wiskott-Aldrich syndrome protein (WASP) gene. In this study, we identified mutations of the WASP gene in 10 Japanese patients from 9 unrelated families with WAS/XLT. All XLT patients (n = 3) and one WAS patient had a missense mutation at the PH domain of WASP. Two WAS patients had nonsense mutations. One WAS patient had exon 8 skipping caused by one nucleotide deletion at the acceptor site of intron 7. Three WAS patients had genomic deletions; one of the three had a large genomic deletion involving exons 3 to 7. Codons 45 and 86 seem to be the hot spots of the WASP mutation, because missense mutations in these codons have been reported previously in several WAS/XLT patients in addition to the patients in this report, and patients with the same mutation show a similar clinical phenotype. All other mutations are novel, indicating that the mutations of WASP are heterogeneous. EB virus-transformed cell lines from XLT patients expressed nearly normal amounts of WASP, whereas those from typical WAS patients expressed almost undetectable amounts of WASP. We conclude that the analysis of gene mutation and protein expression of WASP are useful together in assessing the severity of WAS.     

发热伴血小板减少综合征危重度评分对患者预后的评价

目的：探讨发热伴血小板减少综合征（SFTS）死亡相关因素,设立 SFTS 危重度评分并检验其对 SFTS 患者预后的评价作用。方法对2011年6月至2014年10月山东大学附属济南市传染病医院住院治疗并确诊为 SFTS 的123例患者行死亡相关危险因素的 Logistic 回归分析,进而设定 SFTS危重度评分,并通过受试者工作特征曲线（ROC）与快速急诊内科评分（REMS 评分）、急性生理和慢性健康评分系统Ⅱ（APACHEⅡ）进行预后预测能力的比较。结果123例患者中死亡31例（死亡组）,男17例,女14例;生存92例（生存组）,男45例,女47例。单因素 Logistic 回归分析结果显示,格拉斯哥昏迷（GCS）评分、乳酸脱氢酶、部分活化凝血活酶时间、脉搏血氧饱和度与 SFTS 死亡相关,差异均有统计学意义（均 P ＜0．05）。且4项指标的单项评分,死亡组均高于存活组（均 P ＜0．05）。SFTS 死亡组的REMS、APACHEⅡ评分和 SFTS 危重度评分均高于存活组（均 P ＜0．01）。REMS、APACHEⅡ评分和SFTS 危重度评分的曲线下面积（AUC）分别为0．734、0．746、0．788。Youden 指数以 SFTS 危重度评分为最高,当取阈值为15．0时,其预测 SFTS 患者住院期间死亡风险的敏感度为74．2％,特异度为76．1％。结论 REMS、APACHEⅡ评分和 SFTS 危重度评分对 SFTS 预后均具有良好的评价作用,其中以 SFTS 危重度评分更为简捷且预测能力最佳。