血管性血友病

血管性血友病(von Willebrand disease，vWD)是临床上一种常见的遗传性出血性疾病，其发病机理是患者的血管性血友病因子(von Willebrand factor，vWF)基因突变，导致血浆vWF数量减少或质量异常。vWD相当常见，但轻症患者可无出血表现，故很难准确统计其发病率。国外报道一般在千分之一至五千分之一。     

Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus

von Willebrand disease (vWD), one of the most common bleeding disorders in humans, is manifested as a quantitative or qualitative defect in von Willebrand factor (vWF), an adhesive glycoprotein (GP) with critical hemostatic functions. Except for the rare severely affected patient with a gene deletion as etiology of the disease, the molecular basis for vWD is not known. We studied the molecular basis for vWD in a breeding colony of pigs with a disease closely resembling the human disorder. The porcine vWF gene is similar in size and complexity to its human counterpart, and no gross gene deletion or rearrangement was evident as the pathogenesis of porcine vWD. A restriction fragment- length polymorphism (RFLP) within the porcine vWF gene was identified with the restriction endonuclease HindIII, and 22/35 members of the pedigree were analyzed for the polymorphic site. Linkage between the vWF locus and the vWD phenotype was established with a calculated LOD score of 5.3 (1/200,000 probability by chance alone), with no crossovers identified. These findings indicate that porcine vWD is due to a molecular defect within (or near) the vWF locus, most likely representing a point mutation or small insertion/deletion within the vWF gene.     

Molecular characterization of Iranian patients with type 3 von Willebrand disease

Summary.   von Willebrand's disease (VWD) type 3 is a rare but severe autosomal-recessive inherited bleeding disorder with a prevalence higher in certain locations where consanguineous marriages are relatively frequent. The genetic defects causing recessive type 3 VWD in 10 unrelated families from Iran have been investigated and the genetic heterogeneity among these patients was evaluated. All exons and their flanking regions of von Willebrand factor gene were amplified by PCR and sequenced using specific primers. Eight patients were fully characterized at the molecular level. Six different gene alterations were identified. All the mutations caused null alleles, three being nonsense mutations (Q104X, Q793X and E1981X), two possible splice site mutations (2443-1G>C and 1110-1G>A) and one small deletion (3237delA). Three of them have not been described previously. Most patients were born from consanguineous marriages and all were homozygous for their mutations. The results confirm that molecular defects in type 3 VWD are heterogeneous with mutations arising randomly within the entire gene.     

Acquired von Willebrand disease

Acquired von Willebrand disease (AvWD) is an acquired bleeding disorder which may suddenly become manifest in individuals, usually in the absence of a personal or family history of bleedings and frequently in association with monoclonal gammopathies, lymphoproliferative, myeloproliferative and autoimmune disorders. In a minority of the cases AvWD may develop in association with drugs or solid tumours. Pathogenetic mechanisms involve autoantibodies directed against von Willebrand factor (vWF) resulting in a rapid clearance of vWF from the circulation and/or inactivation of plasma vWF; absorption or adsorption of plasma vWF to malignant cells; drug-induced or cell-mediated proteolysis of plasma vWF; acquired decrease in synthesis of vWF and/or release of vWF from storage sites; or precipitation of plasma vWF. Treatment options include--whenever possible--treatment of the underlying disorder or symptomatic treatment aimed at replacing the loss of vWF by either infusion of vWF-rich concentrates or administration of desmopressin (DDAVP). In selected cases with anti-vWF antibodies, administration of high-dose intravenous gammaglobulin, plasma exchange or extracorporeal immunoadsorption may be successful.     

Acquired von Willebrand disease

Acquired von Willebrand disease (AvWD) is a syndrome that has clinical and laboratory features similar to hereditary vWD. In contrast to the latter it occurs in patients without a family history of previous bleeding tendency.     

Treatment of von Willebrand disease

Summary. von Willebrand disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of treatment is to correct the dual defects of haemostasis, i.e., abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 80% of cases. This pharmacological compound raises endogenous factor VIII and von Willebrand factors and thereby corrects the intrinsic coagulation defect and the prolonged bleeding time in most type 1 patients. In type 3 and in the majority of type 2 patients desmopressin is not effective, and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time after concentrates is associated with continued bleeding.     

Treatment of von Willebrand disease

The bleeding tendency in von Willebrand disease (VWD) is heterogeneous and some patients with the mildest form of the disease have no significant bleeding symptoms throughout their lives. In some cases, the most difficult task for a clinician is to decide whether any treatment is actually required. However, cases with moderate to severe factor VIII (FVIII) and von Willebrand factor (VWF) deficiency usually require treatment to stop or prevent bleeding. Increasing autologous FVIII/VWF by desmopressin administration or providing normal allogeneic VWF through the infusion of plasma-derived concentrates can correct FVIII and VWF deficiencies and normalize or shorten bleeding time (BT). FVIII levels are the best predictors of soft tissue or surgical bleeding, while BT normalization, reflecting the correction of platelet-dependent functions of VWF, is considered a reliable indicator of an effective treatment of mucosal bleeding. Recombinant concentrates of FVIII are not indicated (apart from cases with alloantibodies against exogenous VWF), since they are devoid of VWF and lack its stabilizing effect on circulating FVIII. A very-high-purity concentrate of VWF has recently been made available, but its advantages over conventional concentrates containing both FVIII and VWF moieties are not obvious. The best way to select the appropriate treatment is to perform a test infusion with desmopressin in any patient with clinically significant VWD, provided that he/she has no contraindication to the compound or belongs to subtype with an anticipated lack of response (for example, type 3 VWD with FVIII/VWF lower than 5%).     

Diagnosis of von Willebrand disease

Summary. von Willebrand disease (vWD) is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (vWF). vWF is synthesized by endothelial cells and megakaryocytes and circulates in plasma as a multimeric high molecular weight glycoprotein. vWF plays a major role in the early phases of ostasis by promoting platelet-vessel wall and plateletplatelet interactions under high shear conditions. It is also the carrier of coagulation factor VIII (FVIII) in plasma. A deficiency of vWF results in impairment of both primary and secondary phases of ostasis. Therefore, patients with vWD manifest bleeding symptoms that are typical of defects of primary ostasis (mucocutaneous haemorrhages) but, in case of severe deficiency of vWF, there are also haemarthroses and haematomas, which are typical of those seen with coagulation defects. Several types and subtypes of vWD have been described with a high degree of heterogeneity. The diagnosis is based on measurements of plasma and platelet vWF, the ability of vWF to interact with its platelet receptor and the analysis of the multimeric composition of vWF. Due to the heterogeneity of vWF defects, a correct diagnosis of types and subtypes may be sometimes difficult but is very important for an appropriate treatment of patients with vWD.     

Pseudotumour in von Willebrand disease

Pseudotumour is a rare complication of haemophilia; it has previously been reported in patients with moderate or severe haemophilia and rarely in mild disease. We report a case of a proximal pseudotumour occurring in a 36-year-old patient with mild von Willebrand disease (vWD) who made a good recovery with conservative management. Surgery has been advocated as the optimal treatment for proximal pseudotumours due to the risk of continued bleeding and progression. However, in mild haemophilia or vWD, where the risk of spontaneous bleeds is low, conservative management may be an appropriate alternative.     

Women and von Willebrand disease

In 1926 von Willebrand made the observation that 'the trait seemed especially to be seen among women'. A pictorial bleeding assessment chart (PBAC) defines menorrhagia with a score of >100 representing >80 ml blood loss. A retrospective study has shown menorrhagia in 74% patients with von Willebrand disease (vWD) and vWD in 13% patients with menorrhagia. Although von Willebrand factor (vWF) increases in pregnancy, there may be an increased incidence of post partum haemorrhage. DDAVP is a useful treatment for menorrhagia and postnatally. Clotting factor concentrates containing vWF may be required.     

Prophylaxis in von Willebrand disease

Von Willebrand disease (VWD), the most common hereditary bleeding disorder, is divided into three types depending on the quantitative (type 1 and 3) or qualitative (type 2) abnormality of von Willebrand factor (VWF). About 70–80% of VWD patients can be treated with the synthetic product desmopressin, while the others necessitate factor VIII/VWF concentrates. In addition to the treatment of bleeding episodes, therapeutic regimens include short- or long-term prophylaxis. While the literature data on short-term prophylaxis in VWD are consistent and clearly show the safety and efficacy of such a therapeutic approach, little evidence is available regarding long-term prophylaxis, and although the preliminary results are encouraging, they need to be validated by large prospective studies.     

von Willebrand disease in Finland

The Finnish Red Cross Blood Transfusion Service has served as the national reference laboratory for haemostasis for more than 40 years and remains still the only one in the country to diagnose inherited coagulation factor deficiencies. By September 1997, 1076 patients with von Willebrand disease (vWD) were registered. The severity of bleeding symptoms leading to diagnosis varied according to the type of vWD. After prepubertal phase distinctly more female than male patients were diagnosed. The prevalence of severe type 3 vWD is 4:1 000 000.