Von Willebrand Factor: Biological Function and Molecular Defects

The human von Willebrand factor (vWF) plays a pivotal role in the mechanisms of blood clotting and platelet thrombus formation; it also binds and stabilizes factor VIII procoagulant protein. The biological functions of vWF are dependent on distinct molecular domains responsible for the specificity and affinity for ligands. The multimeric structure of vWF provides an array of binding sites that allow multivalent interactions, thus supporting the formation of stable platelet aggregates at the site of vascular injury, particularly under flow conditions characterized by high shear stress. Quantitative and qualitative abnormalities of vWF cause the most common congenital bleeding disorder in humans, the von Willebrand disease (vWD). This review will provide an update on the recent advances toward the elucidation of structure-function relationships and the detection of molecular defects leading to vWD and will highlight the revised classification of vWD.     

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.     

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.     

New strategies in diagnosis and treatment of thrombotic thrombocytopenic purpura: case report and review

The pentad of thrombocytopenia, haemolytic anaemia, mild renal dysfunction, neurological signs and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults but also children have been described with this condition. The disorder may take a relapsing course, termed chronic relapsing TTP (CRTTP), which although very rare, may also begin in childhood. Deficiency of a recently identified enzyme, the von Willebrand factor (vWF)-cleaving protease, seems to play a major role in the development of TTP. We report on a 3-year-old boy with a dramatic but typical clinical course of CRTTP. At the time of diagnosis, neurological deficits and multiple cerebral infarctions had already occurred. In plasma, vWF-cleaving protease was completely absent, both during acute TTP and in remission. There was no protease inhibitor detected. Regular infusions of fresh frozen plasma were successfully given for replacement on a prophylactic basis. Conclusion Assay of von Willebrand factor-cleaving protease helps to diagnose a form of thrombotic thrombocytopenic purpura which may be managed by prophylactic treatment with fresh frozen plasma. Received: 13 April / Accepted: 4 May 1999     

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.     

Combination of von Willebrand disease type 1 and partial factor XII deficiency in children: clinical evidence for a diminished bleeding tendency

Factor XII deficiency can be associated with a thrombotic and VWF deficiency with a haemorrhagic clinical course. To study the potential influence of factor XII deficiency on bleeding tendency in patients suffering from VWD we retrospectively compared the clinical outcome of children with either an isolated factor XII deficiency, an isolated VWD, or a combination of both. Patients with the combined coagulation defect showed significantly fewer bleeding events when compared to patients with isolated VWD, although ristocetin cofactor activities were reduced to a comparable degree. As far as aPTT values are concerned, there were no significant differences among the three groups. Whether this combination of thrombophilic and haemorrhagic coagulation disorders is only coincidental or the result of an active modulation of one of the two counteracting coagulation factors is not known at present.     

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。     

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.