Immune thrombocytopenia in adults

Immune thrombocytopenia is an autoimmune disease resulting in the destruction of platelets.It is classified as acute,thrombocytopenia occurring for 6 mo and usually resolving spontaneously,and chronic,lasting 6 mo and requiring therapy to improve the thrombocytopenia.The underlying defects leading to autoantibody production are unknown.Molecular mimicry appears to play a role in the development of self-reactive platelet antibodies after vaccination and certain viral infections.Platelet life span is reduced as a consequence of antibody-mediated clearance by tissue macrophages in essentially all patients.Diagnosis is based on the exclusion of the other causes of thrombocytopenia.Steroid is the first choice of the treatment,often followed by splenectomy in unresponsive cases.Intravenous immunoglobulin,anti-Rho(D) immune globulin,azathioprine,cyclosporine A,cyclophosphamide,danazol,dapsone,mycophenolate mofetil,rituximab,thrombopoietin receptor agonists and vinca alkaloids are other choices of treatment.     

应用遗传学分析方法诊断遗传性血小板减少综合征

目的对一血小板减少症伴巨型血小板家系进行遗传学分析,分析其基因突变位点,确定其发病机制。方法采用PCR与测序相结合的方法对血小板减少症家系进行遗传学分析。结果此家系为MYH9基因突变相关的常染色体显性遗传性血小板减少综合征。结论遗传学分析可以辅助确诊遗传性血小板减少综合征。     

Immune thrombocytopenia associated with hemorrhagic diathesis due to ibuprofen administration

Summary Acute thrombocytopenic purpura temporally related to the oral administration of ibuprofen developed in a patient with ankylosing spondylitis. Clinical manifestations, with sudden onset occurring within t2 h of drug ingestion and rapid increase of platelet counts following discontinuation of the drug, were characteristic of an antibody-mediated immune pathomechanism. Immunological studies demonstrated IgM and IgG antibodies in the patient's serum that were capable of binding to allogenic platelets in the presence of a metabolite preparation. This finding suggested that an ibuprofen metabolite, rather then the drug itself, was the antigenic agent responsible for the immune reaction. Despite its widespread therapeutic use, ibuprofen has not been described previously as causing immune-mediated thrombocytopenia.     

The incidence of thrombocytopenia in children with Cornelia de Lange syndrome

Thrombocytopenia was first reported in Cornelia de Lange syndrome (CdLS) by Froster in 1993. Despite early reports, thrombocytopenia has been rarely reported in this disorder. We performed a retrospective analysis of a large cohort of patients with CdLS. We calculated prevalence of thrombocytopenia in three subsets of this cohort: the entire cohort (n = 1,740), a subset of subjects with substantial clinical records (n = 695) and a subset of subjects with clinical information regarding platelet counts (n = 85). This analysis revealed that 15 have had thrombocytopenia (18% of those with available blood counts); seven had immune thrombocytopenia (ITP). The reported prevalence of pediatric ITP is between 5 and 13 per 100,000 persons. The prevalence of ITP in this cohort is between 7/1,740 and 7/85, giving a relative risk of ITP of between 30 (CI 12–77) and 633 (CI 259–1,549). Contrary to the reported cases in the literature, none of our patients have had progression of the thrombocytopenia nor have they developed other cytopenias. All 15 patients with thromobocytopenia had CdLS based on clinical criteria. Of the 10 patients tested for mutations in NIBPL, 8 had mutations identified. These data support an increased incidence of thrombocytopenia and ITP in CdLS. Subsequently, patients are at risk for spontaneous hemorrhage, and likely increased risk secondary to the high frequency of self‐injurious behavior. Although further studies are needed to better define the scope of the problem and to define the mechanisms of thrombocytopenia in CdLS, we would recommend screening for thrombocytopenia upon diagnosis and at 5‐year intervals thereafter. © 2010 Wiley‐Liss, Inc.     

早产儿血小板减少症与母亲胎盘病理特点的关系

目的:探讨早产儿血小板减少症与母亲胎盘病理特点的关系.方法:纳入2015年1月1日至12月31日在广州医科大学附属广东省妇儿医院娩出并入住新生儿重症监护室(neonatal intensive care unit,NICU)72 h内血小板计数小于100×109个/L的单胎早产新生儿(出生胎龄＜37周)作为实验组,并按胎龄匹配纳入同期分娩的血小板计数正常的单胎早产新生儿作为对照组.对胎儿血栓性血管病变(fetal thrombotic vasculopathy,FTV)、胎盘梗塞性病变、脐带扭转、胎盘组织学炎性浸润等胎盘病理特点进行回顾性研究,并对所得数据进行统计学分析.结果:实验组(106例)和对照组(198例)出生胎龄分别为(31.74±2.10)和(31.92±2.06)周,差异无统计学意义(p＞0.05).对照组早产新生儿出生体重[(1 763.59±429.36)g]高于实验组[(1 659.72±422.21)g],差异有统计学意义(P＜0.0s).实验组合并胎盘功能不全情况比例(先兆子痫17.9％,胎儿宫内生长迟缓9.4％)高于对照组(先兆子痫6.1％,胎儿宫内生长迟缓2.5％),差异有统计学意义(P＜0.05).两组胎盘重量[(381.98±107.10)g和(397.05±114.28)g]比较,差异无统计学意义(P＞0.05).实验组FTV的比例(23.6％)及胎盘梗死性改变的比例(35.8％)均高于对照组(分别为12.1％和16.7％),差异均有统计学意义(P＜0.05).实验组脐带扭转及胎盘组织学炎性浸润的比例与对照组比较,差异无统计学意义(P＞0.05).结论:早产新生儿血小板减少症与胎盘梗死性改变及FTV有关,与单纯的胎盘组织炎性浸润情况无关.     

Cutaneous lymphangioma and amegakaryocytic thrombocytopenia in Noonan syndrome

A case of congenital cutaneous lymphangioma and amegakaryocytic thrombocytopenia in an infant with Noonan syndrome is described. These features broaden the phenotype of lymphatic and haematological abnormalities associated with this syndrome.     

The role of HLA antibodies in neonatal thrombocytopenia: a prospective study

The role of HLA antibodies in neonatal alloimmune thrombocytopenia is controversial. We prospectively studied the sera of obstetric patients at delivery for HLA antibodies and correlated their presence with umbilical cord blood platelet counts. We studied 493 births at The Johns Hopkins Hospital comprising of 357 African American, 115 Caucasian, and 21 babies of other racial groups. One hundred and thirty nine mothers had HLA antibodies. Of these HLA alloimmunized mothers, only ten infants had platelet counts of 150,000/μL or less. Three hundred and eight mothers with no detectable antibodies gave birth to 27 infants with platelet counts of 150,000/μL or less. Yates corrected Chi square analysis showed no significant relationship between maternal HLA alloimmunization and baby platelet count (p=0.709). Only 8 of sixty cord sera from babies of HLA alloimmunized mothers were positive for HLA antibodies. The HLA cord blood antibody results were then correlated with the neonatal platelet counts. The Fisher's exact test showed no significant relationship between the presence of HLA antibodies in cord blood samples and neonatal platelet counts (p=0.232). Although one third (31%) of mothers have HLA antibodies, neonatal thrombocytopenia is rarely associated with this finding. However, HLA antibodies can cross the placenta, and in these unusual cases, may be associated with a higher risk of neonatal thrombocytopenia.     

New insights in fetal and neonatal alloimmune thrombocytopenia

During the recent years considerable advances in the clinical and laboratory diagnosis of alloimmune thrombocytopenia have been done. Feto-maternal alloimmunization is the commonest cause of severe isolated fetal and neonatal thrombocytopenia. The condition results from maternal immunization against specific fetal platelet antigens (HPA). Unlike the haemolytic disease of the fetus and newborn the first newborn was found to be affected. The diagnosis is usually made at birth when an otherwise ‘well’ term infant exhibits bleeding at delivery or few hours afterwards. The most feared complication of this disorder is the occurrence of intracranial haemorrhage (ICH) as a result of severe thrombocytopenia leading to death or neurological sequelae. The diagnosis of alloimmune thrombocytopenia enables appropriate management of the index case and future pregnancies. The diagnosis is confirmed by laboratory testing with the identification of the maternal alloantibody and the offending antigen present in the fetus or neonate that is absent in the mother. In a recent retrospective study concerning 75 HPA-1b1b women, we have shown that the diagnosis of maternal alloimmunization was mostly established at delivery and the women were primigravida in 51% of the cases. The deleterious consequence of this severity was evidenced by in utero or postnatal ICH. Subsequent pregnancies were managed according to three different protocols, steroids only, intravenous immunoglobulin (IVIG) or IVIG and steroids. We found that the most efficacious antenatal therapy for fetal alloimmune thrombocytopenia is maternal treatment with IVIG and steroids. In summary, this study shows (1) that the morbidity linked with this condition is important to be considered for further antenatal screening (2) that antenatal management in referral centers should be suggested to high-risk pregnant women.     

Avatrombopag for the treatment of immune thrombocytopenia

Introduction: Thrombopoietin-receptor agonists (TPO-RAs) are the only American Society of Hematology (ASH) guideline-advocated, second-line treatment for immune thrombocytopenia (ITP) that have been validated by randomized, controlled trials with a placebo comparator. Avatrombopag is a new candidate in this class that has been investigated as a treatment option for the treatment of ITP.

Areas covered: In this Drug Profile, we provide a review of the clinical data of avatrombopag, which was approved in May 2018 by the United States Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with chronic liver disease undergoing an invasive procedure, and an opinion of its potential place in the current evidence-based ITP treatment landscape.

Expert commentary: Avatrombopag induces doubling of platelet counts, increasing them to above 50 X 10⁹/L, and prevents the need for platelet transfusions while minimizing the need for rescue medications. Treatment-emergent adverse events (TEAEs) are comparable to placebo. Oral delivery, a 5-day dosing schedule and good tolerability (<1% discontinuation rate) with no clinically significant hepatoxicity make it a promising entrant as a potential second-line treatment for ITP. Further, data from a phase 3 study in patients with ITP supports its utility in the treatment of patients with ITP.     

Foetal and neonatal alloimmune thrombocytopenia (FNAIT)

Thrombocytopenia is detected in around one percent of newborns. In otherwise healthy term newborns, thrombocytopenia is most often caused by alloantibodies transferred from the mother to the foetus. In the Caucasian populations human platelet antigen (HPA)-1a is the most immunogenic HPA. In Japan and China antibodies in the HPA-4 system are the most frequent cause of FNAIT. The immune response against the HPA must be understood in order to avoid immunization or prevent induction of FNAIT where mothers are already immunized.     

DNAJC21-related thrombocytopenia in a young adult female

Bone marrow failure type 3 (BMFS3) (MIM:617052) is a subtype of inherited bone marrow failure syndromes (IBMFS) caused by homozygous pathogenic variants in DNAJC21. It was first defined in 2016, and to date, 19 patients have been reported. Here we report the first adult patient; a 20-year-old female with a novel frameshift variant in DNAJC21 presents with thrombocytopenia, dysmorphic findings, and ovarian agenesis. Our patient expands the clinical spectrum to the milder end and suggests that DNAJC21-related disorders can have relatively mild presentations. Investigation of DNAJC21 variants in both childhood and adult patients with persistent, non-progressive thrombocytopenia will allow to broaden the gene-related phenotypic and genotypic spectrum and elucidate the pathophysiology. Therefore, we encourage revisiting undiagnosed patients to offer whole exome sequencing (WES) in adulthood.     

Prenatal diagnosis of thrombocytopenia with absent radii

Six pregnancies at risk for thrombocytopenia and absent radii (TAR) have been studied between 16 and 20 menstrual weeks utilizing fetal radiography. Two affected and four unaffected fetuses have been correctly identified. Fetal radiography can provide reliable prenatal diagnosis in pregnancies at risk for TAR.     

218例妊娠合并血小板减少临床分析

目的探讨妊娠合并血小板减少的围产期处理及产后出血情况。方法收集2006年1月至2011年8月茂名市人民医院及广州医学院第三附属医院收治的218例妊娠合并血小板减少患者,根据分娩前血小板计数51×109-99×109／L、21×109-50×109／L、≤20×109／L分为A、B、C三组,每例患者针对原发病治疗,产前根据病情适当给予糖皮质激素,静脉注射丙种球蛋白,输入血小板治疗,分析各组的产后出血情况。结果A、B、C三组的产后出血发生率分别为2．67％、7．46％、28．20％;平均出血量分别为（600±80）、（600±120）、（900±200）ml,产后24h平均阴道流血量分别为（250±30）、（250±80）、（500±100）ml,C组平均出血量及24h平均阴道流血量与A、B组比较,差异均有统计学意义（P〈0．05）。结论妊娠合并血小板减少,在治疗原发病的基础上,给予对应治疗,适时终止妊娠可有效改善不良妊娠结局。     

Fetal and neonatal alloimmune thrombocytopenia: from bench to bedside

During the recent years considerable advances in the clinical and laboratory diagnosis of alloimmune thrombocytopenia have been done. Feto-maternal alloimmunization is the commonest cause of cause of severe isolated fetal and neonatal thrombocytopenia. The condition results from maternal immunization against specific fetal platelet antigens (HPA). HPA-1a is mostly implicated in Caucasians. The diagnosis is usually made at birth when an otherwise “well” term infant exhibits bleeding at delivery or few hours afterwards. The most feared complication of this disorder is the occurrence of intracranial hemorrhage (ICH) as a result of severe thrombocytopenia leading to death or neurological sequels. The diagnosis of alloimmune thrombocytopenia enables appropriate management of the index case and future pregnancies. Due to the recurrence and increasing severity of this condition in subsequent pregnancies with incompatible fetuses, antenatal management has been proposed. Predictive maternal parameters for severe fetal thrombocytopenia and therapy effectiveness are important for the development of non- invasive strategy.     

Anti-thymocyte globulin induced thrombocytopenia

Anti-thymocyte globulin is strongly reactive with platelets as measured by flow cytometric analysis. This reactivity appears to be independent of human leukocyte antigen (HLA) phenotype, is dose-dependent with saturation of platelet binding sites readily achieved with concentrations of horse anti-thymocyte globulin (ATG) at 0.25 mg per ml, and cannot be blocked with human anti-PLA1 antibody nor with heat-aggregated human IgG. Results of immunoblot studies after electrophoresis of platelet membrane proteins are consistent with the proposal that horse ATG contains antibodies specific for platelet glycoproteins V and IIa.     

急性免疫性血小板减少动物模型的实验研究

目的：制备急性免疫性血小板减少动物模型。方法：采用洗涤小鼠血小板免疫家兔获得抗小鼠血小板血清（APS）；将74只BALB／c小鼠随机分为3组：对照组（10只）、APS组（32只）、正常家兔血清（NRS）组（32只）。对照组经尾静脉注射灭菌生理盐水100ul，APS组经尾静脉注射1：4浓度抗小鼠血小板血清APS100ul，NRS组经尾静脉注射正常家兔血清100ul。每组均于注射前和注射后第3、6、12小时取小鼠尾静脉血，进行血小板。白细胞及红细胞计数，并测定每个时间点断尾出血时间。结果：APS组外周血象显示各时间点血小板计数进行性减少，出血时间进行性延长，第3、6、12小时所测血小板计数值与NRS组及对照组比较亦差异显著（p〈0．01），而红细胞和白细胞计数无显著变化（p〉0．05）。NRS组、对照组各时间点及组间血小板计数、出血时间、白细胞计数、红细胞计数均无显著差异。结论：用免疫血清法制备急性免疫性血小板减少模型方法可行，可靠，成功率高。     

Amegakaryocytic thrombocytopenia and immune-mediated haemolytic anaemia in a cat

An eleven-month-old female spayed domestic shorthair cat was presented for investigation of pruritic skin lesions and haemorrhage. Haematological evaluation revealed a markedly regenerative anaemia, neutrophilia with left shift, monocytosis, basophilia and severe thrombocytopenia. The direct antiglobulin test and serum antinuclear antibody tests were positive. Serologic and immunofluorescent antibody tests for feline leukaemia virus were negative. Bone marrow cytology revealed a lack of megakaryocytes with erythroid and myeloid hyperplasia. A peritoneopericardial diaphragmatic hernia was detected ultrasonographically, but was not considered to be related to the haematologic abnormalities. An immune-mediated aetiology for the amegakaryocytic thrombocytopenia was considered likely based on the concomitant positive direct antiglobulin and antinuclear antibody tests, but the cat responded poorly to short-term immunosuppressive therapy and was euthanized.