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血管性血友病

Von Willebrand Disease

作者信息

Johnsen Jill

机构信息

Division of Hematology and Oncology, Department of Medicine;, Institute for Stem Cell & Regenerative Medicine;, Center for Cardiovascular Biology, University of Washington, Seattle, Washington

Abstract

CLINICAL CHARACTERISTICS

Von Willebrand disease (VWD) is characterized by mucocutaneous bleeding and excessive bleeding with trauma and procedures. Individuals with more severe forms of VWD are also at-risk for musculoskeletal bleeding. Mucocutaneous bleeding can include easy bruising, prolonged bleeding from minor wounds, epistaxis, oral cavity bleeding, heavy menstrual bleeding, gastrointestinal bleeding, and bleeding with hemostatic challenges such as dental work, childbirth, and surgery. Bleeding severity can vary widely in VWD, even between affected individuals within the same family. For some with VWD the bleeding phenotype may only become apparent upon hemostatic challenge, while others may have frequent spontaneous bleeding.

DIAGNOSIS

The diagnosis of VWD is established in a proband with excessive bleeding by identification of a quantitative or qualitative deficiency in von Willebrand factor (VWF) and/or identification of a VWD-causative variant(s) in by molecular genetic testing.

MANAGEMENT

VWF replacement; desmopressin. People with VWD benefit from care in a comprehensive bleeding disorders program. Treatment is often given on demand for active bleeding episodes or for prevention of bleeding with hemostatic challenges. Prophylaxis should be considered in those with more severe bleeding. Useful adjunctive hemostatic treatments include antifibrinolytics, hormonal therapies for female reproductive tract bleeding, and local anatomic measures. Antifibrinolytic treatment (e.g., tranexamic acid) can be used alone for some hemostatic challenges or in combination with VWF-increasing treatment. Hormonal treatments can be useful in managing female reproductive tract bleeding either alone or in combination with antifibrinolytics and/or VWD-specific treatment. Assessment in a center experienced in the comprehensive management of bleeding disorders to determine bleeding frequency and severity, treatment efficacy and tolerability, CBC, iron levels, VWF levels, and VWF inhibitors in those at risk (type 3 VWD) annually in those receiving treatment or every two to three years in those without bleeding and not requiring treatment. Evaluation by a physiotherapist, including consideration of musculoskeletal ultrasound evaluation for those with more severe VWD and/or low factor VIII levels, to monitor joint health (as in individuals with hemophilia A). Gynecology evaluation as needed for females with heavy bleeding. Gastroenterology evaluation with any suspected gastrointestinal bleeding or per gastroenterologist. Infectious disease assessment as needed in those exposed to blood products prior to 1985 or with other risk factors. Activities with a high risk of trauma; high contact sports with risk of head injury; medications with effects on platelet function (e.g., aspirin, clopidogrel); nutritional supplements that may impair hemostasis (e.g., fish oil, turmeric); invasive procedures without prior consultation with a hematologist (e.g., circumcision, dental, dermatologic, piercings). NSAIDs can increase bleeding risk and should be used cautiously and only for brief periods. It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual to allow early diagnosis and treatment as needed. In newborns, assess cord blood for low VWF and factor VIII levels to inform neonatal treatment. Molecular genetic testing of cord blood can be informative, particularly if the familial VWD-causing variant(s) are known. Monitor VWF and factor VIII levels throughout pregnancy; postpartum hemorrhage prophylaxis with antifibrinolytics unless contraindicated; VWF replacement can be used to increase VWF levels.

GENETIC COUNSELING

Type 1, type 2A, and type 2M VWD are typically caused by a heterozygous variant and inherited in an autosomal dominant manner; rarely, these VWD types are associated with biallelic variants. Type 2B VWD is typically caused by a heterozygous variant and inherited in an autosomal dominant manner. Type 2N and type 3 VWD are caused by biallelic variants and inherited in an autosomal recessive manner. Many individuals diagnosed with autosomal dominant VWD have an affected parent. Each child of an individual with autosomal dominant VWD has a 50% chance of inheriting the VWD-causing variant. VWD often exhibits variable penetrance and expressivity. If both parents are known to be heterozygous for a VWD-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial VWD-causing variants. Heterozygous sibs of an individual with type 2N VWD are often asymptomatic; however, a small proportion of these heterozygous individuals may have some mild bleeding symptoms and lower factor VIII levels and may be diagnosed with VWD. Heterozygous sibs of an individual with type 3 VWD may be asymptomatic or may have bleeding symptoms and low VWF levels and may be diagnosed with type 1 VWD. Molecular genetic testing for at-risk relatives is most informative if the VWD-causing variant(s) have been identified in an affected family member. Once the familial VWD-causing variant(s) have been identified, prenatal and preimplantation genetic testing for VWD are possible.

摘要

临床特征

血管性血友病(VWD)的特征是皮肤黏膜出血,以及外伤和手术时出血过多。病情较重的VWD患者还存在肌肉骨骼出血风险。皮肤黏膜出血可表现为容易出现瘀斑、小伤口出血时间延长、鼻出血、口腔出血、月经过多、胃肠道出血,以及在进行牙科治疗、分娩和手术等止血挑战时出血。VWD患者的出血严重程度差异很大,即使是同一家族中的患者也是如此。对于一些VWD患者,出血表型可能仅在止血挑战时才会显现,而另一些患者可能会频繁出现自发性出血。

诊断

通过识别血管性血友病因子(VWF)的定量或定性缺陷,和/或通过分子基因检测识别VWD致病变异,在有出血过多情况的先证者中确立VWD的诊断。

管理

补充VWF;去氨加压素。VWD患者在综合出血性疾病项目中接受护理会受益。治疗通常根据需要用于治疗活动性出血发作或预防止血挑战时的出血。对于出血较严重的患者应考虑进行预防性治疗。有用的辅助止血治疗包括抗纤溶药物、针对女性生殖道出血的激素疗法以及局部解剖学措施。抗纤溶治疗(如氨甲环酸)可单独用于某些止血挑战,或与增加VWF的治疗联合使用。激素治疗单独或与抗纤溶药物和/或VWD特异性治疗联合使用,可能有助于管理女性生殖道出血。在有经验的出血性疾病综合管理中心进行评估,以确定出血频率和严重程度、治疗效果和耐受性、全血细胞计数、铁水平、VWF水平,以及有风险者(3型VWD)的VWF抑制剂,接受治疗的患者每年评估一次,未出血且无需治疗的患者每两到三年评估一次。由物理治疗师进行评估,包括对病情较重的VWD患者和/或因子VIII水平较低的患者考虑进行肌肉骨骼超声评估,以监测关节健康(如同甲型血友病患者)。有月经过多的女性根据需要进行妇科评估。有任何疑似胃肠道出血或根据胃肠病学家建议进行胃肠病学评估。1985年之前接触过血液制品或有其他风险因素的患者根据需要进行传染病评估。有高创伤风险的活动;有头部受伤风险的高接触性运动;对血小板功能有影响的药物(如阿司匹林、氯吡格雷);可能损害止血的营养补充剂(如鱼油、姜黄);未经血液科医生事先咨询的侵入性操作(如包皮环切术、牙科、皮肤科、穿孔)。非甾体抗炎药会增加出血风险,应谨慎使用且仅短期使用。对受影响个体的明显无症状的有风险亲属进行评估是合适的,以便根据需要进行早期诊断和治疗。对于新生儿,评估脐带血中VWF和因子VIII水平以指导新生儿治疗。脐带血的分子基因检测可能会提供有用信息,特别是如果已知家族性VWD致病变异。在整个孕期监测VWF和因子VIII水平;除非有禁忌证,用抗纤溶药物预防产后出血;可使用VWF替代物来提高VWF水平。

遗传咨询

1型、2A型和2M型VWD通常由杂合变异引起,以常染色体显性方式遗传;这些VWD类型很少与双等位基因变异相关。2B型VWD通常由杂合变异引起,以常染色体显性方式遗传。2N型和3型VWD由双等位基因变异引起,以常染色体隐性方式遗传。许多被诊断为常染色体显性VWD的个体有一位患病的父母。常染色体显性VWD个体的每个孩子有50%的机会继承VWD致病变异。VWD通常表现出可变的外显率和表达度。如果已知父母双方都是VWD致病变异的杂合子,受影响个体的每个兄弟姐妹在受孕时有25%的机会患病,50%的机会为杂合子,25%的机会既不继承家族性VWD致病变异。2N型VWD个体的杂合子兄弟姐妹通常无症状;然而,这些杂合子个体中有一小部分可能有一些轻微出血症状和较低的因子VIII水平,可能被诊断为VWD。3型VWD个体的杂合子兄弟姐妹可能无症状,或可能有出血症状和低VWF水平,可能被诊断为1型VWD。如果在受影响的家庭成员中已识别出VWD致病变异,对有风险亲属进行分子基因检测最具信息价值。一旦识别出家族性VWD致病变异,就可以进行VWD的产前和植入前基因检测。

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