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W1507714927 abstract "In 1926, Erik von Willebrand, a Finnish internist and academic, evaluated and described a 5-year-old girl with extreme bleeding and bruising due to what had been designated the ‘Ålandic haemorrhagic disease’ by inhabitants of this archipelago island in the Gulf of Bothnia. Hjørdis, the propositus, was the ninth of 12 children born to a pedigree in which four female siblings had already died before the age of 4 with uncontrolled haemorrhage and in which 23 of 66 family members, predominantly females, had experienced significant bleeding and bruising complications [1]. In fact, Hjørdis herself eventually died at the age of 13 during her fourth menstrual cycle. Professor von Willebrand mistakenly concluded that this bleeding diathesis was an unusual form of haemophilia and decided to label the new disease as ‘pseudo-haemophilia’ to differentiate it from the sex-linked recessive haemophilia A. Little did von Willebrand realize that this disease, eventually to become eponymous [von Willebrand disease (VWD)], would become the most commonly diagnosed congenital bleeding disorder, with a prevalence ranging between 1 per 10 000 individuals to 1.3% [2]. Type 1 VWD is the most common subtype, representing up to 75–80% of all cases while the subtype 3 VWD occurs in approximately 1 per million population in the United States and Europe [2]. Determination of the exact prevalence of VWD is hindered somewhat by the heterogeneity of clinical and diagnostic laboratory features. Even Professor von Willebrand appreciated the challenges of diagnosing VWD as he collaborated with Professor Rudolf Jügens at the Berlin University to examine patients’ blood samples with a newly invented ‘kapillärtrombometer’ apparatus [3]. Although they were technically mistaken when they attributed the bleeding manifestations of VWD to a platelet defect, their observations were remarkably prescient since it was not until early 1970s that the existence of a specific von Willebrand factor (VWF) glycoprotein separate from factor VIII was finally appreciated and demonstrated to support platelet adhesion to the subendothelial matrix of damaged blood vessels. Over the last 81 years since von Willebrand described the bleeding disorder, there have been numerous attempts and approaches to refine the diagnosis of the disease so that appropriate and efficacious treatment can be delivered. The clinical phenotype of VWD includes, in part, information on whether bleeding is spontaneous or related to surgical or physical trauma; family history and inheritance pattern; menstrual history in women; age of onset of bleeding (to distinguish between acquired vs. inherited coagulation disorders); and sites of bleeding (mucocutaneous vs. visceral, intra-articular, intramuscular, or soft tissue locations). Subsequent laboratory testing is necessary to exclude or confirm the diagnosis and to further classify the subtype of VWD. This article will focus on selected vagaries associated with the ability to utilize clinical phenotypic information gathered through the history and physical examination to predict the presence of VWD. The clinical diagnosis of VWD must be based, however, on more than physician suspicion and intuition. Thus, the need for confirmatory testing in the laboratory. The frailties of conventional laboratory testing for diagnosing VWD and the use of an in vitro surrogate of the bleeding time will also be discussed. The capability to perform genetic testing increases the sensitivity and specificity of the VWD diagnostic panel of laboratory assays and is the ultimate holy grail. Finally, therapeutic decisions are predicated on the correlation of phenotypic characteristics with laboratory confirmation. What improvements can we anticipate, which will enhance our VWD therapeutic armamentarium for the future? The diagnosis of von Willebrand disease is based on the presence of a personal history of clinically significant and excessive mucocutaneous bleeding, a family history of excessive bleeding associated with an autosomal inheritance pattern, and laboratory confirmation of a quantitatively and/or qualitatively abnormal von Willebrand factor protein. The process of ascertaining the clinical history and determining whether the features of bleeding and bruising warrant referral of the patient for laboratory evaluation and confirmation of the presence of VWD are not as straightforward as they might seem. von Willebrand himself appreciated the heterogeneity and variability of clinical bleeding and bruising in individuals with VWD, particularly those with moderate and mild severity symptomatology. Sadler noted that non-specific bleeding symptoms, occasionally significant, commonly occur in healthy individuals (prevalence conservatively estimated to be 25%) but also are the basis for diagnosing a bleeding diathesis consistent with type 1 VWD [4]. He further argues that population screening utilizing questions to identify bleeding symptoms has overestimated the prevalence of medically significant bleeding diatheses and concludes that ‘most diagnoses of VWD type 1 are false positives’ [4]. The possibility that more specific and discriminating history taking might decrease the false positive rate of VWD diagnosis rate has prompted the development of numerous bleeding indices and scoring systems, which could be applied in a uniform manner to screen for significant bleeding in a primary care setting. Tables 1 and 2, published as part of the Consensus Guidelines for the Diagnosis and Treatment of von Willebrand Disease by the National Heart, Lung and Blood Institute of the National Institutes of Health in the United States, provide a summary of data compiled from multiple published studies, intended to quantify bleeding symptoms in almost 1000 normal healthy individuals and over 1800 with various subtypes of VWD [5]. Overall, these data attest to the fact that the prevalence of mild bleeding symptoms, whether mucocutaneous, haemarthroses, or soft tissue in nature, is essentially equivalent in mild VWD types 1 and 2 as in normal individuals. In contrast and not unexpectedly, severe type 3 VWD patients tend to experience significantly more serious bleeding complications from all sites and all categories of bleeding. Maximum predictive sensitivity for the ability to diagnose VWD is conveyed by positive responses to inquiries about family members with bleeding symptoms (odds ratio = 28.6) and/or established diagnoses of bleeding diatheses (odds ratio = 97.5) or profuse bleeding after general (odds ratio 23) or dental surgery (odds ratio = 39.4) or from small wounds (odds ratio = 67.2). Women with VWD are more likely to manifest frequent gingival (odds ratio = 76.5) and dental extraction bleeds (odds ratio = 54.9), epistaxis (odds ratio = 61.8), or peripartum haemorrhage (odds ratio = 50.0). These compiled observations reflect the findings of other very well designed and meticulously performed independent surveys, such as the large prospective multicentre European VWF study [6]. Recently, a bleeding severity score derived from a detailed questionnaire administered to patients has been standardized in normal individuals and in cases with VWD type 1, but it can be useful for all VWD types and for other inherited and acquired bleeding disorders [7]. The clinical history obtained from individuals who present with bleeding problems ideally should determine whether the patient should be referred to the laboratory for confirmatory testing. Population screening studies, such as described above, certainly indicate the prevalences of clinical characteristics in individuals with bleeding disorders; however, the great overlap in symptoms between healthy normal and mild type 1 VWD cohorts remains great and necessitates adding more objective genotypic and/or laboratory information to increase the specificity of the diagnosis. The physical examination provides important confirmatory information for the diagnosis and treatment of VWD. The presence of ecchymoses, soft tissue haematomas, and physical evidence of mucocutaneous bleeding, e.g. epistaxis, is consistent with VWD. In contrast, increased joint and skin laxity and widened, poorly organized scars suggest Ehlers-Danlos syndrome; intramuscular haematomas and intra-articular bleeding are characteristic of the haemophiliac (and severe type 3 VWD). The presence of petechiae is more likely due to thrombocytopenia than to VWD. The thrombocytopenia associated with VWD type 2B, which is induced by variant VWF with increased binding affinity to platelet membrane glycoprotein, does not usually produce petechiae (see Table 1). The development of telangiectasias, representative of possible systemic angiodysplasia, is considered an uncommon physical complication of VWD but when they do occur, they may become increasingly apparent on physical examination with aging and may potentially contribute to increased symptomatic mucocutaneous bleeding from the nose, gastrointestinal and genitorurinary tracts. A point mutation of exon 28 in the A1 domain of the VWF gene on chromosome 12 (amino acid substitution; Arg 543→Trp) has been associated with significant bleeding from gastrointestinal angiodysplasia and is located immediately adjacent to two previously identified type 2A VWD mutations [8,9]. Telangiectasias may also be associated with other disease states, such as scleroderma and ataxia telangiectasia. Improvement or reversal of the bleeding manifestations found on physical examination is a sensitive indicator of successful replacement therapy in VWD. The laboratory diagnosis of VWD has conventionally been accomplished by performing a panel of assays as the individual assays lack sensitivity, are often difficult to reproduce between laboratories, and may vary in conjunction with genetic and physiologic conditions. The individual with a history of excessive bleeding or easy bruising is typically referred for laboratory screening for coagulopathies in general and VWD specifically. Thus, the activated partial thromboplastin test (aPTT), prothrombin time (PT), thrombin time, fibrinogen concentration and platelet count are global measures of coagulation but usually are the initial entry points for any algorithmic approach to the laboratory evaluation and diagnosis of bleeding disorders and VWD. While a prolonged aPTT may suggest the presence of the reduced factor VIII coagulant activity (FVIII:C), which occurs as part of VWD, a normal aPTT or FVIII:C does not necessarily exclude the diagnosis of mild VWD. Decreased FVIII:C levels in VWD reflect the deficient capacity of VWF to function as an adequate qualitative or quantitative chaperone of FVIII:C in the plasma rather than reduced synthesis of FVIII:C as in haemophilia A. Quantitatively defective VWF cannot protect FVIII:C from accelerated clearance from the circulation or from accelerated in vivo proteolysis. Similarly, qualitatively defective VWF, as in VWD variant type 2 Normandy, cannot complex with FVIII:C by virtue of its mutated FVIII binding sites on the D’ and D3 domains [10]. The platelet count is an important component of the screening workup as both the number and morphology can be used to identify platelet-derived bleeding disorders, e.g. giant size and decreased numbers in Bernard-Soulier syndrome, and to classify VWD subtypes, e.g. giant size and thrombocytopenia in VWD 2B and pseudo-VWD. The bleeding time (BT) had traditionally been considered an important element of the initial laboratory diagnosis of VWD; however, the accuracy and reproducibility of this test are well known to be technician dependent and the technique is difficult to standardize. Furthermore, BT results have been shown to be non-specific for the diagnosis of VWD when they are prolonged, are not sensitive enough to detect mild cases of VWD (although BT is probably satisfactory for diagnosis of severe type 3 VWD), and are not predictive of bleeding tendency. Clinical studies in severe type 3 VWD have demonstrated that the BTs did not completely normalize even after the administration of FVIII/VWF concentrates corrected the markedly low VWF activities in plasma. Federici noted that the BT should not be expected to completely correct in VWD as replacement of VWF with exogenous FVIII/VWF concentrates, regardless of their functional activities and VWF multimer content, cannot completely replenish the VWF deficiency located within the endothelial cells, bound to components of the subendothelial matrix, or contained in the alpha granules of platelets of patients with VWD [11]. Consequently, the BT has fallen from favour to diagnose VWD or to monitor the adequacy of its treatment. Surrogate assay systems have been developed in an attempt to circumvent the vagaries of the BT and to simulate and quantitate the rheologic and biologic interactions of VWF with platelets and collagen. Ideally, such assays should be simple to use, reproducible, and sensitive to the multimeric composition of VWF and VWF activity levels. The PFA-100 (Platelet Function Analyzer, Dade-Behring, Marburg, Germany) has been introduced as an automated technique to screen for VWD and has also been utilized to monitor the therapeutic efficacy of replacement therapy. Tables 3a and b delineate features of the PFA-100 pertinent to the diagnosis of VWD. This device attempts to simulate the high shear rates in vivo by drawing up whole blood via standardized vacuum into disposable cartridges containing a fine capillary coated with collagen (fibrillar type 1 equine tendon) and either epinephrine (CEPI) or adenosine diphosphate (CADP) as agonists for platelet aggregation [12,13]. A platelet plug is formed after platelet adhesion to collagen and subsequent aggregation occur. This process occludes the capillary and generates the Closure Time (CT) as the measurable endpoint (in seconds) of the assay. The CTs is influenced primarily by platelet function and VWF levels and to some degree by the concentration of citrate (3.2% citrate preferable for VWD results). In addition, CTs are prolonged by thrombocytopenia (<100 000/μL), anaemia (haematocrit <28%), and leucopenia. CEPI is very sensitive to aspirin but the CADP is insensitive. The most common causes of an abnormal CADP test are heart aortic valve disease, severe vessel stenosis, renal failure and VWD. Since the first three will be clinically obvious, appropriate follow up is a platelet aggregation/release profile and VWF activity and antigen determinations [12,13]. The sensitivity of the PFA-100 approaches 100% for VWD types severe 1, 2A, 2M, and 3 [14], but is insensitive to variant type 2N and variably sensitive to type 2B. PFA-100 results in mild or moderate type 1 VWD may not be abnormal [14–17], with published sensitivities ranging from 50–100% [14]. BT and PFA-100 results may be discordant in detecting VWD with PFA-100 being more sensitive and more correlated to specific VWF functional assays, particularly the VWF collagen binding test (VWF:CB) [14]. Some studies indicate that PFA-100 results are difficult to reproduce with published reports indicating up to 20% variability [18]. Coefficient of variability for PFA-100 testing is difficult to ascertain since the assays are rarely performed in duplicate. Perhaps the major limitation for the use of the PFA-100 apparatus in VWD is the fact that it is insensitive to the incremental increases of VWF activities following the administration of FVIII/VWF concentrates for therapeutic replacement [14]. The explanation for this is not entirely clear; however, it may be related to fact that FVIII/VWF concentrates contain considerable amounts of fibrinogen and other integrin proteins, which interfere with direct platelet-capillary membrane-fibrillar collagen surface interactions or which alter the rheology of capillary flow in the system. In contrast, the PFA-100 can detect the haemostatic improvement after DDAVP [desmopressin; sold commercially as Stimate® (desmopressin acetate) nasal spray, 1.5 mg/ml; CSL Behring, King of Prussia, PA, USA] administration both in individuals with VWD and qualitative platelet dysfunction [14]. In addition, abnormal PFA-100 results are very non-specific, indicating either VWD, thrombocytopathies, or medication effects (especially aspirin). The PFA-100 cannot diagnose VWD. Any prolonged PFA-100 result should trigger definitive testing in the laboratory for VWD, including the measurement of VWF:Ag, VWF:RCo, FVIII, and perhaps VWF:CB, platelet aggregation, and VWF multimers. On the other hand, any normal PFA-100 result essentially excludes the presence of severe VWD or platelet dysfunction and renders this assay system useful for broad screening. For example, in a study of 108 women with significant menorrhagia being screened for contributing coagulopathies, the PFA-100 detected an unexpectedly high prevalence of platelet defects (>25%) vs. 6% with VWD [18]. There is mixed enthusiasm for the use of the PFA-100 in the screening process for diagnosis of VWD worldwide, with greater skepticism expressed by the NHLBI Consensus panel, which stated that the currently available data do not support its routine use [5]. There is greater endorsement for the PFA-100 expressed by others, who advocate inclusion of the PFA-100 assay in their VWF diagnostic algorithms [14,16]. When the findings of an extensive personal and family history suggest the presence of a pattern of mucocutaneous bleeding, laboratory corroboration is necessary before the diagnosis of VWD can be established. The global screening laboratory tests discussed above lack the specificity or sensitivity to diagnose VWD or its subtypes, although severe type 1 and type 3 VWD should always produce abnormalities in these test systems. Laboratory confirmation of VWD requires the demonstration of quantitative and/or qualitative deficiencies of VWF structure and function. VWF:Ag assays provide a quantitative measure of protein concentration in plasma without providing information on function or multimeric structure. This assay cannot be used by itself to diagnose VWD. Since VWF:Ag is basically performed as an immunoassay, it possesses good precision and reproducibility, in contrast to the VWF:RCo assay, which assesses VWF capacity to interact with glycoprotein 1b/IX complex on the surface of normal platelets in the presence of the antibiotic ristocetin. This assay and its ‘variations on the theme’ are considered functional assays for VWF and they are somewhat sensitive to VWF multimeric composition. On the other hand, the VWF:RCo assay does not simulate any true physiologic event since there is no in vivo equivalent of ristocetin. Rather, the high shear rates, which occur in the microvasculature, stimulate the conformational changes and unfolding of the VWF molecule in vivo and, in turn, mediate VWF interactions with the platelet. In practice, there are many different commercial kits for VWF:RCo measurement; each has its own technical limitations, particularly at low levels of VWF:RCo activity. There is significant inter and intra laboratory variability of results. The United Kingdom National External Quality Assessment Scheme for Blood Coagulation reported a coefficient of variation (CV) up to 64% among an expert group of International Haemophilia Treatment Centres for a sample of VWF:RCo of 11 IU/dL [19]. Because of the imprecision among functional VWF:RCo assay methods, other assays which provide information on VWF multimeric integrity have been developed. The VWF collagen binding assay (VWF:CB) is ELISA based and measures the selective ability of binding sites on the A3 domain of the highest molecular weight multimers of VWF to interact with fibrillar collagen. Unfortunately, these assays also possess imprecision by virtue of the fact that their sensitivities are influenced by the type and sources of fibrillar collagen (type I or III or a combination I/III from horse or bovine) used in the assay. Favaloro claims that type I collagen and type I/III collagen mixtures used in the VWF:CB assay preferentially detect high molecular weight multimers better than human type III or bovine type I collagen preparations [20]. He further states that the VWF:CB assay is preferred over VWF:RCof assays (if only one functional VWF assay is to be performed) because it can detect the type 2 variants more consistently than VWF:RCo assays, because it is more reproducible than VWF:RCo assays, and because it is more sensitive to low levels of VWF activity [20]. Most laboratories, which have set up the assay, choose to use the VWF:CB assay to supplement rather than to replace the VWF:RCo assay so that type 2 variants will not be overlooked. Surveys indicate that the VWF:CB is performed more frequently in Australasia than in Europe and North America. Other ancillary assays which are useful to subclassify VWF include low dose ristocetin induced platelet rich plasma aggregation (RIPA) assays (to detect VWD variant 2B), VWF:FVIII binding (VWF:FVIIIB) assay to diagnose the VWD 2Normandy variant, and the VWF multimeric analysis, which depicts the qualitative (and somewhat quantitative) distribution of VWF multimeric bands and helps to define the VWD subtypes with multimeric defects. Fig. 1 depicts the idealized relationships between quantitative VWF assays (functional and immunological) and their relative abilities to detect VWF multimer distribution and the qualitatively defective VWF structures associated with the variant subtypes of VWD [20]. VWF:Ag detects all molecular weight forms of VWF while VWF:RCo and VWF:CB assays are more selectively sensitive to detect the high molecular weight multimeric forms. In theory, the VWF:CB assay is more selective in detecting the largest of the high molecular weight VWF multimers compared to the VWF:RCo assay. Von Willebrand Factor (VWF) structure and function: quantitative VWF assays (functional and immunological) do not predict VWF multimeric composition (adapted from ref. 20). The considerable imprecision of each of the assays employed for the diagnosis of VWD and the large intra- and inter-laboratory coefficients of variability associated with performing them can be mitigated by performing panels of assays. This will allow for the evaluation of VWF structure and function. Including the FVIII activity assay in the panel will offer important information on the severity of VWD (severe type 1 and type 3 are characterized by very low FVIII activity) and the potential to bleed from VWD. A survey conducted by the Royal College of Pathologists in Australasia indicated that >95% of laboratories performed at least one functional VWF assay with approximately 40% performing both VWF:RCof and VWF:CB assays [21]. A mild type 1 VWD unknown plasma was distributed to 48 laboratories and there was almost a seven fold likelihood of misdiagnosis of this sample as a type 2 variant if a VWF:CB assay was not performed (VWF:CB without VWF:RCo = 5%; VWF:CB performed with VWF:RCo = 3.0%; VWF:RCo without VWF:CB = 23%). The critical role of the VWF:CB assay to increase the accuracy of VWD diagnosis also was corroborated when type 2 VWF plasmas were examined (VWF:RCo without VWF:CB misdiagnosed 28.1%; VWF:CB without VWF:RCo = 4.8%; VWF:CB with VWF:RCo = 11.3%). Only 8.5% of type 3 samples were misdiagnosed and VWF:CB did not improve the diagnostic accuracy over the VWF:RCo assay [21]. Figure 2 summarizes the benefits of applying multiple VWF assays to improve the accuracy of VWD diagnosis. The significant usefulness of including VWF:CB assays in the diagnostic laboratory panel. The diagnostic laboratory panel for von Willebrand disease (VWD) may benefit from the inclusion of the VWF:CB assay [adapted from Ref 21]. An additional approach which may increase the accuracy of VWD diagnosis involves the use of VWF:CB/VWF:Ag or VWF:RCo/VWF:Ag ratios. These ratios may provide an additional tool to distinguish the type 2 variants from type 1 VWD [22,23]. Because of the larger coefficients of variability associated with VWF:RCo assays compared to VWF:Ag and VWF:CB assays, the VWF:CB/VWF:Ag ratio may be more accurate and discriminatory, but larger studies are needed to confirm this. At this time, a VWF:CB/VWF:Ag ratio of ≤0.5 and VWF:RCo/VWF:Ag ratio of ≤0.7 separates VWD type 2A and 2B from normal or type 1 VWD plasmas [22,23]. The VWF:CB/VWF:Ag ratio may provide more discriminatory power to distinguish between type 2A and 2B (Fig. 3) [22]. The use of VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios to increase the diagnostic accuracy of type 2 VWD [adapted from Ref. 22]. There are also important preanalytical variables which can significantly influence the accuracy of VWD diagnosis in the laboratory (Table 4). Probably the most critical of these involves specimen collection and handling. Flawless venipuncture will limit the amount of tissue factor release and activation of proteases, which may activate FVIII and affect VWF structure and function and lead to spuriously high activity levels. EDTA added to the collection tubes may minimize this; however, FVIII levels cannot be ascertained in this type of anticoagulated plasma. If plasma samples are to be frozen for delayed testing, they should be centrifuged in advance to create platelet poor plasma so that the alpha granular content of VWF and residual platelet membranes will not interfere with laboratory assays to diagnose VWD. On the other hand, the high molecular weight multimers of VWF are very sensitive to time and temperature of storage. Storage of plasma and whole blood at room temperature for more than 4 h and refrigeration storage may be associated with degradation and proteolysis of the multimeric structure of VWF and may lead to false positive diagnosis of mild VWD and/or the misidentification and misclassification of a type 2 variant in an otherwise mild type 1 VWD individual [24–26]. This is illustrated in Fig. 4 [26]. The high molecular weight multimers of von Willebrand factor (VWF) are very sensitive to time and temperature of storage. Storage of plasma and whole blood at room temperature for more than 4 hours and refrigeration storage may be associated with degradation and proteolysis of the multimeric structure of VWF. This may lead to false positive diagnosis of mild VWD and/or the misidentification and misclassification of a type 2 variant in an otherwise mild type 1 VWD individual. (Adapted from ref. 26.) Epigenetic factors also may lead to false positive or negative diagnoses of VWD in the laboratory (Tables 4 and 5). These include such variables as possessing blood group O, use of oestrogen containing medications and pregnancy, increasing age, hypothyroidism, stress, extreme exercise, and the presence of prosthetic heart valves. When assessing for VWD, these factors should be considered since they may produce fluctuating VWF results. Recently, single nucleotide polymorphisms (SNP) in the 5′-regulatory region of the VWF gene have been associated with elevated plasma concentrations of VWF:Ag, VWF:RCo, and VWF:CB activity [27,28]. There is no definitive evidence as yet that the Thr789Ala and nucleotide -1793 SNPs in the von Willebrand factor gene increases the long term risk for developing coronary artery disease [28]. In contrast, the VWF polymorphism Tyr/Cys1584 has been associated with variably decreased levels of VWF:Ag, VWF:RCo, and VWF:CB activities. This mutation is located within the A2 domain of VWF where cleavage by ADAMTS13 occurs, explaining its increased susceptibility to proteolysis by ADAMTS13 [29]. It remains to be determined if any ADAMTS13 polymorphisms exist which provide a gain or loss of function adequate enough to affect circulating VWF activities. DDAVP, a synthetic vasopressin analog, has been used successfully for treatment and prevention of bleeding complications associated with VWD since the late 1970’s. Experience has demonstrated that type 3 and many severe type 1 VWD do not respond to DDAVP and that its use in individuals with variant type 2B could be dangerous because of thrombocytopenia and the formation of circulating platelet aggregates. Several studies now suggest that the pattern of response to DDAVP in vivo might enhance the ability to diagnose VWD variants and could be complimentary to VWF multimeric analysis. Federici et al. have provided seminal information on the relationship between DDAVP responsiveness, phenotype, and genotype [30]. For example, they demonstrated that there was a difference in the pattern of DDAVP response in those with VWD 2A due to intracellular processing defects vs. those due to increased extracellular proteolysis of VWF. The former defect was characterized by greater improvement in VWF:RCo and bleeding time results [30]. Patients with variant 2M were poorly responsive; however, there was a transient correction of the VWF:RCo/VWF:Ag ratio that correlated to a shortening of the bleeding time. This response is characteristic of the VWD 2M defect in which the multimeric composition is normal but the interaction of the defective VWF with platelets is abnormal, thus reduced VWF:RCo/VWF:Ag at baseline and unsustained correction of the ratio by 2 h after DDAVP [30]. The responses to DDAVP in individuals with the special subtype 2M Vicenza VWD, which has abnormally large molecular weight multimers circulating in plasma but phenotypically reduced VWF activities, low FVIII, and prolonged bleeding times. Following intravenous DDAVP, these 2M patients demonstrated marked shortening of their prolonged bleeding times, conveyed by the release of ultra high molecular weight multimers, but their FVIII and VWF:RCo activities were not sustained. This pattern of response may be due to accelerated clearance of DDAVP-released VWF [31,32]. Accelerated clearance of FVIII was noted after DDAVP administration to individuals with VWD 2N (Normandy), in whom baseline VWF activities are normal and increase appropriately with DDAVP; however, the marked incremental rise of FVIII activity from baseline low levels is not sustained because of defective binding to its abnormal circulating chaperone (VWF) and subsequent accelerated clearance from the circulation. Because of the heterogeneity in laboratory and clinical phenotype, the imprecision of laboratory testing of VWF function and structure, and physiologic and epigenetic influences on VWD phenotype, e.g. hormonal, blood type, malignancy, etc., the availability of a ‘molecularly assisted classification system’ [33] for VWD would correlate phenotype with genotype and lead to more precise diagnosis and individualization of therapeutic strategies. Now that the VWF gene structure and location (chromosome 12 short arm containing 52 exons spanning 178 kb) are known, this possibility becomes more likely. However, the fact that over 130 single nucleotide polymorphisms have been already been identified in the large and complex VWF genome indicates that this approach practically and realistically will not be easy to implement. (see registry of VWF mutations on the ISTH Scientific Subcommittee VWF Information Homepage, a database maintained at the University of Sheffield, UK; http://www.shef.ac.uk/vwf). Furthermore, a partial pseudogene copy of the VWF gene exists on chromosome 22, which potentially confounds the interpretation of polymerase chain reaction amplification. Recently, closer linkage has been established between the genetic abnormalities and variable phenotypes associated with type 1 VWD [34]. In a Canadian cohort study, 78 (63%) of 123 type 1 VWD cases were associated with VWF with 50 different putative gene mutations, of which the clear majority (62%) were missense in nature. Interestingly, 10–20% of cases had more than one putative VWF mutation [34]. The Y1548C missense mutation on the D3-A3 domain predominated in this cohort (13%) and appears to have been corroborated in a European cohort (around 10%) as well [35]; however, a cause–effect explanation is lacking. Genetic changes were detected in the more clinically severe cases and were highly penetrant whereas the mild cases appeared to be influenced by non-VWF gene determinants, e.g. ABO blood group, etc. Genetic testing for type 2 VWD is slightly more rewarding as putative gene mutations are associated with cause-effect explanations. For example, most of the missense mutations associated with VWD 2A appear to be responsible either for aberrant A2 domain structure in the VWF protein, which is most susceptible to ADAMTS13 mediated proteolysis, or to defects in the D3 domain, which is critical to normal VWF multimer assembly and intracellular transport. Similarly, most of the gene mutations associated with VWD 2B are located in the A1 domain, which contains the glycoprotein 1b/IX binding complex. These mutations have led to ‘gain of function’ characteristics. The ability to detect this particular gene mutation would allow the physician to distinguish between VWD type 2B vs. pseudo-VWD, which would not possess a VWF gene mutation, but would be expected to be associated with a platelet glycoprotein 1b/IX mutation [36]. Missense mutations in the A1 domain at sites different from VWD 2B have predominated for VWD 2M although the Vicenza 2M subtype has been associated with D3 domain defects [36]. The D3 domain defect leads to ‘loss of function’ for platelet interaction with VWF. Much clinical utility has arisen from the ability to detect missense mutations in the D’ region of the VWF protein since these account for the vast majority of VWD 2N variants. The presence of this mutation, along with the confirmatory laboratory testing for VWF binding to FVIII, is important in distinguishing this VWD variant from phenotypically mild or moderately severe haemophilia A [36]. Genetic testing for severe type 3 VWD is not as easy as might be expected. Certainly, the diagnosis is apparent from the genetic and phenotypic presentation and laboratory function abnormalities for VWF and FVIII activities; however, the mutational basis of this subtype is heterogeneous, ranging from frameshift mugations in exon 18 (perhaps the most common mutation) to large gene deletions to missense mutations [36]. The large gene deletions would be most likely to be associated with development of alloantibodies to VWF replacement. The availability of genetic techniques to detect severe type 3 disease in utero could reduce the morbidity of intracerebral haemorrhage in the fetus after delivery. Clearly, genetic testing would provide diagnostic and clinical clarity to VWD; however, from the therapeutic perspective, our imagination has been captured by the allure of future VWD replacement therapy strategies employing products which are genetically engineered. Currently, in the United States, there are two viral attenuated, plasma derived FVIII concentrates (Humate P®, CSL Behring, King of Prussia, PA, USA; AlphaNate SD/HT®, Grifols, Los Angeles, CA, USA) which have been licensed by the Food and Drug Administration for use in VWD replacement and another one (Koate DVI,® Talecris Research Triangle Park, NC, USA), which is used off label. In Germany, there is a licensed high purity, double viral inactivated (solvent detergent and terminal high heat treated), pooled plasma FVIII/VWF concentrate (Wilate,® Octapharma AG, Lachen, Switzerland), which was developed to provide a VWF:RCof complex ratio of 1.1, which is physiological. Although they are all considered members of the same drug class, they are not equivalent products for the treatment of VWD since they each possess a different spectrum of VWF molecular weight multimers and different ratios of VWF:RCof/FVIII activity (Humate P ≈ 2; AlphaNate SD/HT≈0.5; Koate DVI≈1.2; Wilate≈1.1). All commercially available FVIII/VWF concentrates lack a fraction of the high-molecular-weight multimers found in normal plasma and the multimeric pattern of VWF which is detected in the plasma of VWF patients after infusion reflects the defective multimeric pattern of the concentrate used. Nevertheless, clinical trials substantiate their efficacy. The VWF:RCof/FVIII properties of these products is important clinically as they may provide for more precise dosing regimens aimed at preventing the excessive accumulation of FVIII in plasma after repeat administration and thus minimizing the potential of thrombotic complications during VWD replacement therapy. Although thrombotic events are rare in patients with VWD receiving repeated infusions of FVIII/VWF concentrates, there is some concern that sustained high concentrations of FVIII:C may increase the risk of postoperative venous thromboembolism. It is recommended to maintain FVIII activity between 50 U/dl and 150 U/dl, particularly in the postoperative period as FVIII/VWF is being replaced [37]. Such complications may be avoided if a very high purity VWF concentrate with little FVIII content is used (Wilfactin®; LFB, Les Ulis, France), but then extra care must be given to co-administer a ‘priming’ dose of FVIII concentrate in emergency situations to assure adequate haemostasis [38]. The recent development of recombinant canine [39] and murine [40] VWF constructs for animal model studies and promising results with infusions of recombinant human VWF concentrates into pigs with severe von Willebrand disease[41] provide the proof of principle that genetically engineered VWF could eventually become a commercial product for VWF replacement therapy. There is debate among clinical experts as to whether the final construct and product should be composed of both recombinant FVIII and VWF or just VWF. Little did Professor von Willebrand realize 81 years ago that the family he described would be the basis for the most common of the congenital bleeding disorders. The current scientific and commercial efforts to further elucidate the structure and function of the VWF gene and protein and to translate that information into new paradigms and products for the diagnosis and treatment of VWD will be exciting to watch and benefit from." @default.
W1507714927 created "2016-06-24" @default.
W1507714927 creator A5063213136 @default.
W1507714927 date "2007-12-01" @default.
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W1507714927 title "Diagnosis and treatment of von Willebrand disease: new perspectives and nuances" @default.
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