The diagnosis and treatment of von Willebrand disease in children

von Willebrand disease is the most common bleeding disorder seen in children and it affects approximately 1% of the population. Because the bleeding symptoms in von Willebrand disease are generally mild, the diagnosis is often delayed. Prompt diagnosis and management can help to avoid potentially life-threatening bleeding events and unnecessary exposure to blood products. In this review, the various types of von Willebrand disease are outlined, the difficulties in diagnosis are discussed and the therapeutic approach to this common disorder is described.     

Glycogen storage disease type Ib: familial bleeding tendency

A mild bleeding tendency with characteristics of the von Willebrand disease was documented in family members of a girl with glycogen storage disease type Ib (GSD) Ib). It was assumed that a defective glucose-6-phosphate dependent microsomal glycoprotein synthesis was involved in the bleeding disorder of the patient and the GSD Ib heterozygotes.Abbreviations GSD Ia glycogen storage disease type Ia - GSD Ib glycogen storage disease type Ib - G6P glucose-6-phosphate - G6P-ase glucose-6-phosphatase     

儿童重型遗传性血管性血友病2 例临床分析

目的分析儿童重型遗传性血管性血友病(VWD)的临床特征及基因变异。方法回顾分析2例VWD患儿的临床资料,采用免疫比浊法检测血管性血友病因子(VWF)活性。采集患者及其父母的外周血,通过高通量基因测序,分析F7、F8、F9、F11、VWF基因全部外显子编码区和剪接区的变异情况。采用PCR结合Sanger测序的方法,分析VWF基因位点的变异情况。结果 2例男性患儿,分别为1岁和2岁,临床表现以皮肤黏膜出血为主,血管性血友病因子活性(VWF:Act)分别为5.0%及2.8%。例1血浆因子Ⅷ凝血活性(FⅧ:C)1.9%、血浆因子ⅩⅡ凝血活性(FⅩⅡ:C)43.2%;例2 FⅧ:C 23%。例1 VWF基因检测到c.813CG(p.Tyr271Ter)纯合变异;父母均为杂合变异。例2 VWF基因检测到c.55GA(p.Gly19 Arg)和c.1200 CA(Asp400Glu)杂合变异,分别来自其父亲、母亲。c.813CG(p.Tyr271Ter)变异与3型VWD相关;c.55GA(p.Gly19 Arg)变异率极低,与1型VWD相关;c.1200 CA(Asp400Glu)变异未见报道,SIFT、Polyphen和MutationTaster均预测其有致病性。2例患儿经止血及替代治疗后,病情均有所好转。结论经基因检测确诊重型1型和3型VWD各1例,并发现VWF基因c.1200 CA(Asp400Glu)新发变异。     

Therapeutic consequences for misdiagnosis of type 2N von Willebrand disease

Patients presenting with a low FVIII:C and with normal VWF levels are usually presumed to have hemophilia (males) or be carriers for hemophilia (females). Some of these patients may instead have VWD:2N. Such patients if misdiagnosed are likely to suffer from insufficiently treated bleeds. We report 2 males and 1 female who presented with a low FVIII:C (1-21%) and minimally reduced/normal VWF and were assumed to have, or be a carrier for, hemophilia A. Eventually all were found to have VWD:2N. Prior to the correct diagnosis the males had been treated with rFVIII with poor responses and ultimately adverse clinical consequences.     

Management of type 2b von Willebrand disease in the neonatal period

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting one in 1,000 people. Type 2b VWD is a less common subtype caused by a gain‐of‐function mutation in von Willebrand factor (VWF) that leads to the formation of large, ineffective VWF‐platelet multimers in circulation. This unique pathophysiology creates diagnostic and treatment dilemmas. There is limited information on the management of type 2b VWD in the neonatal period. This report describes the management of a neonate with type 2b VWD with an emphasis on the added benefit of concomitant platelet transfusion and factor replacement therapy over factor replacement therapy alone.     

A case of inherited type 1 and type 2A von Willebrand disease confirmed by diagnostic exome sequencing

A 10‐year‐old male and his family members visited a pediatric hematology clinic due to coagulopathy. Laboratory tests indicated von Willebrand disease (vWD) in all the family members. We conducted diagnostic exome sequencing for confirmation. The patient was confirmed to be a compound heterozygote for vWD: c.2574C > G (p.Cys858Trp) from his father (known variant of vWD type 1) and c.3390C > T (p.Pro1127_Gly1180delinsArg) from his mother (variant known to result in exon 26 skipping in vWD type 2A). He was managed with factor VIII and von Willebrand factor complex concentrate during palatoplasty due to bleeding despite pre‐operative desmopressin injection. The operation was completed successfully.     

血浆vW因子抗原检测在儿童感染性休克中的意义

目的　 探讨血浆vonWillebrandFactorAntigen(vWf :Ag)在儿童感染性休克中的临床意义。 方法 　用ELISA方法检测 9例休克死亡组、11例休克存活组及 10例健康对照组患儿血浆vWf:Ag(vW因子抗原 ) ,同时用酶比色法检测这 2 0例感染性休克患儿的动脉血乳酸。 结果 　血浆平均vWf :Ag休克死亡组 (710 9± 3 9 4) %明显高于休克存活组 (5 94 5± 5 8 6) % (P<0 0 0 0 1)和健康对照组 (93 8± 16 1) % (P <0 0 0 0 1)。 2 0例休克患儿血浆平均vWf:Ag(64 6 9± 77 3 9) %与平均动脉血乳酸浓度 (3 96± 1 0 0 5 )mmol/L呈正相关 (r =0 886) ,与器官衰竭数目亦成正相关 (rs=0 92 9)。 结论 　vWf:Ag的测定可以作为血管内皮损伤标志物和感染性休克发展为多脏器功能衰竭的一个预警指标     

新生儿硬肿症血浆血管性假血友病因子的意义

目的 探讨新生儿硬肿症血浆血管性假血友病因子(vWF)的意义.方法 采用免疫浊度法检测39例新生儿硬肿症和11例正常新生儿血浆vWF水平.结果 硬肿症组血浆vWF明显高于对照组(P＜0.005),轻度硬肿组与对照组比较无显著性差异(P＞0.05),中、重度硬肿组血浆vWF均明显高于对照组(P均＜0.05),且血浆vWF升高与硬肿症程度相一致;血浆vWF与血pH呈负相关(r=-0.808 P＜0.001).结论 中、重度硬肿症体内存在以高凝为主的早期DIC,血管内皮细胞损伤参与其病理生理过程.     

Utility of thromboelastography for the diagnosis of von Willebrand disease

Von Willebrand disease (VWD) is an inherited bleeding disorder that is caused by a quantitative or qualitative deficiency of von Willebrand factor (VWF). The National Heart, Lung, and Blood Institute (NHLBI) guidelines for the diagnosis of VWD state that a VWF activity (VWF:RCo) of <30 IU/dL or <50 IU/dL with symptoms of clinical bleeding are consistent with the diagnosis of VWD. However, current gold‐standard diagnostic testing takes days to have complete results. Thromboelastography (TEG) is a testing method that provides a graphical trace that represents the viscoelastic changes seen with fibrin polymerization in whole blood, therefore providing information on all phases of the coagulation process. This study describes the TEG characteristics in 160 patients who presented for workup of a bleeding disorder and a subset of those were subsequently diagnosed with VWD. The TEG parameters, K‐time (representing the dynamics of clot formation) and the maximal rate of thrombus generation (MRTG), were found to be sensitive in detecting patients with VWF:RCo <30 IU/dL. The TEG, unlike VWF:RCo, can be done in real time, and results are available to the clinician within an hour. This will definitely be beneficial in acute situations such as evaluation of and management of acute bleeding in patients with acquired deficiencies of VWF and may play an important role in the surgical management of patients with VWD.     

Continuous infusion of von Willebrand factor and factor VIII after elective heart surgery in a 12-year-old girl with von Willebrand disease type 3

The continuous infusion of von Willebrand factor (VWF) in a 12-year-old girl with type 3 von Willebrand disease is described. The patient had elective heart surgery with cardiopulmonary bypass for closure of her atrial septum defect. The surgical procedure lasted 3 h. A presurgical bolus followed by a postoperative continuous infusion of factor VIII/VWF concentrates was administered. During the continuous infusion of clotting factors, stable plasma levels of hemostasis and avoidance of dangerously low levels of factor concentrates were achieved. No peri- or postsurgical complications occurred. Continuous infusion of clotting factors allows constant and hemostatic factor concentrations to be maintained with the possibility of dose titration and adjustment.     

Low von Willebrand factor in pediatric patients: Retrospective analysis of 293 cases informs diagnostic and therapeutic decision making

Low von Willebrand factor (VWF) poses diagnostic and therapeutic challenges for predicting bleed risk and need for empiric hemostatic therapy, particularly in children. Retrospective review identified 293 low VWF pediatric patients and investigated clinical and laboratory features. Low activity to antigen ratio was observed in 142 patients. When evaluation included VWF activity with gain‐of‐function glycoprotein Ib fragments (VWF:GPIbM) assay or VWF exon 28 sequencing, low VW was excluded in the majority (62%) of these patients. Application of a condensed bleeding assessment tool to quantify bleeding symptoms and use of the VWF:GPIbM assay may reduce the number of patients with bleed risk anxiety and unnecessary hemostatic management plans.