Diagnosis and treatment of von Willebrand disease

Hematol Oncol Clin N Am 18 (2004) 1277 – 1299

Diagnosis and treatment of von Willebrand disease Joan Cox Gill, MDa,b,c,* a

Departments of Pediatrics and Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA b Comprehensive Center for Bleeding Disorders, 5019 North Executive Drive, Peoria, IL 61614-4866, USA c The Blood Center of Southeastern Wisconsin, P.O. Box 2178, Milwaukee, WI 53201-2178, USA

In 1926, Eric von Willebrand [1] first described the hemorrhagic disorder that is now known as von Willebrand disease (VWD) in people who were living on ¨ land Islands off the coast of Finland. Since then, numerous investigators the A have applied increasingly sophisticated scientific technologies to define the pathophysiology, molecular biology, genetic inheritance, diagnosis, and treatment of this highly variable disorder of the large complex plasma protein, von Willebrand factor (VWF). VWF serves two roles in hemostasis following injury to the vessel wall; it functions as a mediator of platelet adhesion to damaged endothelium and it serves as a carrier protein for coagulation factor VIII (FVIII) in the formation of a fibrin clot. Qualitative or quantitative defects of either or both functions result in a hemorrhagic disorder of variable severity and manifestations. The diagnostic classification, and ultimately, the effective management of VWD, is dependent on the ability of the clinician to understand the function of VWF and the pathologic consequences of the qualitative and quantitative defects of the molecule.

Pathophysiology VWF is a large, multimeric protein that is synthesized as a protein composed of 2791 amino acids, pro-VWF (Fig. 1). Pro-VWF is cleaved into the VWF propeptide, also known as VWF antigen II [2] and mature VWF, a 230-kd * The Blood Center of Southeastern Wisconsin, P.O. Box 2178, Milwaukee, WI 53201-2178. E-mail address: [email protected] 0889-8588/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.hoc.2004.07.006

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Fig. 1. Protein structure for VWF and its large propolypeptide. Domains of VWF have high degrees of similarity; various protein interactions have been localized to specific regions of the molecule, such as the interaction of GP1b or IIb/IIIa. The lower portion represents the clusters of DNA mutations that cause the variants of VWD, including types 2A, 2B, 2M, and 2N and less common variants that prevent cleavage of the propolypeptide (hereditary persistence of pro-VWF; hereditary persistance of pro-VWF [HPP-VWF]) or a variant that prevents amino-terminal multimerization (type 2-md). (Courtesy of R.R. Montgomery, MD, Milwaukee, WI.)

monomer that is assembled through disulfide-linked bonds into multimers that range in size from approximately 500 kd dimers to 20 million dalton multimers. The largest multimers are necessary for normal platelet adhesion [3–5]. VWF is synthesized in endothelial cells and megakaryocytes and is stored in secretory granules, the Weibel-Palade body in endothelial cells, and the a-granule in platelets [6,7]. The propeptide circulates as a dimer in plasma. At the time of vascular injury, particularly in mucocutaneous vessels of high shear stress, VWF binds to ligands in the subendothelial matrix and promotes adhesion of platelets by way of interaction with the platelet glycoprotein (GP)Ib and GPIIb/IIIa receptors [8–11]. Platelets are then activated, secrete the contents of their granules, and recruit additional platelets to the site, which interact with fibrinogen through the GP IIb/IIIa receptor to form a platelet plug [12]. Thus, individuals who lack the largest VWF multimers, either because of a deficiency of VWF protein or abnormal molecular structure/function, have a defect in platelet plug formation because of failure of normal platelet adhesion and aggregation. The deficiency of platelets at the site of vascular injury in VWD also results in impaired fibrin formation because the platelet provides the surface upon which coagulation factors are activated to generate the fibrin clot. VWF also functions as a carrier protein for FVIII:C (coagulation factor VIII) in the circulation and stabilizes the molecule [13] by protecting it from in-

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activation and clearance [14]. In severe VWD, the lack of VWF results in a secondary deficiency of FVIII, which is cleared rapidly in the absence of VWF [15]. Thus, individuals who lack normal amounts of VWF or have impaired FVIII binding to VWF may have decreased fibrin formation as well as abnormal platelet adhesion and aggregation.

Classification and genetics The VWF gene, located on chromosome 12, contains 52 exons that span 178 kilobases (kb). [16–18]. See Fig. 1 for the relationship between the complementary DNA to structure and functional regions of the VWF protein. VWD is the result of quantitative (type 1 or 3) or qualitative (type 2) defects in VWF (Table 1). It is one of the most common inherited bleeding disorders, is believed to be present in up 2% of the population, and occurs in all racial groups [19–21]. Accurate estimates of the prevalence of VWD are hampered by its highly heterogeneous nature and variable expression [22]. Type 1 VWD is an autosomal dominantly inherited partial quantitative defect that results in decreased amounts of normally functioning VWF (hypoproteinemia). It is the most common form of VWD and accounts for 70% to 80% of cases [16–18]. Patients are affected variably, many have only mild symptoms and a mildly decreased VWF level, whereas others are affected more severely. Some of the variability is explained by the specific VWF mutation which may cause a dominant negative effect on expression of the normal allele [23–28] or there may be undetected compound heterozygosity. Genetic modifiers also may affect the expression of VWD; the most well-characterized is the effect of ABO blood group on VWF levels [29]. Individuals of blood group O have mean VWF levels approximately 75% of normal, whereas those of group AB have 123% of normal levels; patients of group A (105% of normal levels) and group B (117% of normal levels) are affected intermediately. Expression of genetic polymorphisms of the collagen receptor which results in differential density of the receptor on platelets also may affect the severity of bleeding symptoms in type 1 VWD [30]. Population differences in VWF levels were shown to affect the diagnosis of VWD in African American women [31]. Other potential genetic modifiers are being investigated. Type 3 VWD is a complete quantitative defect (aproteinemia) with undetectable VWF and a severe bleeding phenotype. Generally, it is the result of autosomal recessive or compound heterozygous inheritance; it is rare and occurs in 1 in 250,000 individuals. Genetic mutations are generally null mutations that are located throughout the gene; large deletions, frame shift, or nonsense mutations have been reported [32–34]. Affected patients have undetectable plasma VWF and reductions of FVIII:C to less than 3% to 5%. Type 2 VWD, which is characterized by qualitative defects in VWF (dysproteinemias), is subdivided into four subtypes: 2A, 2B, 2M, and 2N (see Table 1) [35,36]. Type 2A VWD is the most common of the type 2 variants; more

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VWD type

Prevalence

Pathophysiologic characteristics

Diagnostic von Willebrand factor assays

Type 1

1–2% of general population; 70–80% of VWD 1:250,000 10% of diagnosed VWD Rare 20% of Type 2 VWD

Decreased amount of normal VWF

Proportionally decreased VWF:RCo and VWF:Ag with normal multimers; factor VIII:C variably decreased Absent VWF:RCo, VWF:Ag, and VWF multimers; factor VIII:C 3–5% Decreased VWF:RCo, normal or decreased VWF:Ag, absent high and intermediate molecular weight multimers Decreased VWF:RCo, normal or decreased VWF:Ag, absent high molecular weight multimers, increased RIPA at low-dose ristocetin, increased VWF binding to normal platelets, thrombocytopenia Decreased VWF:RCo, normal or decreased VWF:Ag, normal VWF multimer structure, decreased VWF binding to normal platelets Normal VWF:RCo, normal VWF:Ag, normal VWF multimer structure, decreased factor VIII:C, decreased factor VIII binding to VWF Decreased VWF:RCo, normal or decreased VWF:Ag, absent high molecular weight multimers, increased RIPA at low-dose ristocetin, normal VWF binding to normal platelets, thrombocytopenia

Type 3 Type 2A

Type 2M

Rare

Complete absence of VWF Failure of mutant VWF to multimerize or increased proteolysis of mutant VWF Adsorption of high molecular weight mutant VWF multimers from plasma due to increased binding to platelet GP 1b Abnormal VWF binding site for platelet GP 1b

Type 2N

Rare

Abnormal VWF binding site for factor VIII

Platelet-type

Rare

Adsorption of high molecular weight VWF multimers from plasma due to increased binding to mutant platelet GP 1b

Type 2B

Abbreviation: RIPA, ristocetin-induced platelet aggregation.

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Table 1 Classification of von Willebrand disease

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than 20 point mutations have been identified in exon 28 of the VWF gene that result in failure of multimer assembly or a change in the conformation of VWF that is associated with increased sensitivity to proteolysis [34,37–39]. Several previously classified rare variants have been reclassified as type 2A; one variant (previously type IIC), which is characterized by an increase in VWF dimers, is located in the D1 loop (see Fig. 1) [34]. Type 2B VWD accounts for less than 20% of type 2 VWD and is the result of spontaneous binding of VWF to platelets [40,41]. The phenotype is characterized by loss of the high molecular weight multimers from plasma and thrombocytopenia because of the spontaneous agglutination and clearance of platelets from the circulation as a result of the abnormal VWF binding. Most cases are due to a point mutation in the VWF A1–loop that contains the GP1b-binding domain; this results in the unique ‘‘gain of function’’ mutation (see Fig. 1). Type 2B VWD must be distinguished from platelet-type VWD, which is due to mutations in the gene that encodes the platelet GP1b receptor and results in increased binding to the high molecular weight multimers of VWF [42–45]. The phenotype is similar to type 2B VWD except the defect is in the platelet, rather than the VWF; the increased binding in either case results in loss of the high molecular weight multimers from plasma and thrombocytopenia. Type 2M VWD variants also are characterized by mutations in the GP1bbinding domain of VWF but result in a ‘‘loss of function’’ with failure of the mutant protein to bind normally to platelet GP1b [46–48]. Unlike type 2A VWD, in which the loss of function is due to the absence of high molecular weight multimers, patients who have type 2M VWD have normal multimeric structure but the multimers are qualitatively abnormal. Hereditary persistence of pro-VWF, a rare variant with normal multimers, is caused by a mutation located in the DV region of the molecule that prevents propolypeptide cleavage (see Fig. 1) [49]. Type 2N VWD is the result of a mutation in the FVIII binding domain at the N-terminus of VWF [50–53]. The disorder is characterized by decreased FVIII in the circulation that is due to increased clearance of unbound FVIII; this results in a decreased FVIII:VWF ratio in plasma. Phenotypically, the defect resembles mild hemophilia A and is the cause of so-called ‘‘autosomal hemophilia.’’ It may be misdiagnosed as hemophilia A and the diagnosis of type 2N VWD should be considered in families with affected girls/women. The phenotype seems to be expressed in the presence of a second allele that carries type 1 VWD, or rarely, homozygosity for type 2N VWD (see Fig. 1).

Diagnosis Clinical presentation Typically, patients who have VWD present with symptoms of mucous membrane bleeding, such as epistaxis, ecchymoses, menorrhagia, and excessive bleeding with surgical or other invasive procedures. Excessive bleeding with

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adenotonsillectomy is a frequent presentation in childhood [54]. Attempts have been made to quantify the amount of bleeding that is necessary to be considered pathologic, but in mildly affected patients the Scientific and Standardizations Committee of the International Society on Thrombosis and Haemostasis’ (SSC/ ISTH) provisional definition (1996 Annual Report of the SSC/ISTH Subcommittee on VWF) may be too stringent and exclude patients who are affected by the disorder. Therefore, investigators have modified the definitions, particularly for those in the pediatric age group [55] in whom injuries and surgical procedures that may precipitate hemorrhage are limited. Because excessive bruising and epistaxis may occur in normal individuals, the identification of severe recurrent epistaxis or ecchymoses in unusual places may be more suggestive of an underlying bleeding disorder. Petechiae are associated more commonly with platelet function defects; however, some patients who have VWD present with petechiae, particularly if aspirin or other nonsteroidal anti-inflammatory medications have been ingested. Large hematomas are more characteristic of hemophilia or severe VWD. Menorrhagia is a frequent presentation in women; in a large series, 15% to 20% of women who had documented menorrhagia were found to have an inherited bleeding disorder [56]. Adolescents who present with menorrhagia frequently are affected as well [57]. Iron deficiency in association with blood loss from epistaxis or menorrhagia should trigger an evaluation for an underlying bleeding disorder. VWD was reported in association with hemorrhagic telangiectasia (Osler-Weber-Rendu) syndrome; telangiectasias should be sought in patients who have recurrent epistaxis or gastrointestinal bleeding [58]. In patients who have mild VWD, stress and inflammation that are associated with certain operations (eg, ruptured appendix) may reduce symptoms, whereas minor surgery in the nonstressed patient may be associated with severe bleeding. It is important to establish a positive family history in the diagnosis of VWD; a careful family history should reveal bleeding symptoms similar to the propositus in each generation. It is a requirement for diagnosis in the provisional guidelines that were set forth by the SSC/ISTH because VWD is inherited in an autosomal dominant fashion. Although men and women are affected equally, women may be recognized more often because of menorrhagia and excessive bleeding with childbirth. Screening assays Traditional screening assays for VWD, including the partial thromboplastin time (PTT) and bleeding time, lack sensitivity and specificity and are normal in more than 50% of patients who have mild or moderate type 1 VWD (unpublished data). Generally, the PTT is abnormal only if the FVIII is decreased significantly or a second coagulation factor defect (eg, factor IX or factor XII) is present. The platelet count is decreased only in type 2B VWD or platelet-type VWD. More recently, the Platelet Function Analyzer (PFA-100, Dade-Behring, Newark, Delaware), an instrument that measures ex vivo platelet binding to collagen/ epinephrine or collagen/ADP, was shown to be more sensitive and specific;

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however, false positive and false negative readings have been seen [55,59–61]. Therefore, in the patient who has a positive personal and family history, a definitive diagnosis of VWD is dependent upon assays of VWF quantity, structure, and function. Definitive laboratory assays See Table 1 for a summary of assay patterns in the classification of VWD types. Quantitative immunoassay for von Willebrand factor antigen The quantity of VWF in plasma is measured with a variety of quantitative immunoassays (VWF:Ag). The most widely used are the ELISA and the quantitative immunoelectrophoretic assay (Laurell assay) [62,63]. Both provide an estimate of the quantity of VWF protein in plasma but do not measure function or structure of VWF. Functional assays of von Willebrand factor The activity of VWF is measured most often using the antibiotic, ristocetin, hence the term ‘‘ristocetin cofactor assay’’ (VWF:RCo) [64,65]. Ristocetin induces the binding of VWF to the GP1b receptor on platelets. Initially, the assay was performed using a platelet aggregometer; when ristocetin is added to a mixture of patient plasma (or dilutions of standard plasma) and formalin-fixed normal platelets, the slope of the agglutination curve is proportional to the amount of VWF activity in plasma (Fig. 2). Recently, various methods were developed to automate the assay. Decreased VWF:Rco, in the presence of normal VWF:Ag, is indicative of dysfunctional VWF binding to GP1b (types 2A, 2B, and 2M VWD), whereas, proportional decreases in both assays are indicative of a quantitative decrease of a normally-functioning VWF molecule (type 1 VWD). If the two assays are standardized carefully, the ratio of VWF:RCo to VWF:Ag may be used to diagnose type 2M VWD (Fig. 3). Collagen binding of plasma to VWF has been the basis of several assays of VWF function (termed collagen binding assay; VWF:CBA). The assays are affected by the type of collagen that is used [66,67]. Decreased collagen binding in proportion to the VWF antigen assays is supportive of a dysfunctional VWF molecule; however, the assay is sensitive to the multimeric structure of VWF [68]. Therefore, the assay frequently is normal in patients who have type 2M VWD in whom decreased binding of platelets to GP1b is not due to absent high molecular weight multimers of VWF. Ristocetin-induced platelet aggregation In contrast to the ristocetin cofactor assay in which the patient’s plasma is mixed with normal platelets, in the ristocetin-induced platelet aggregation assay, various concentrations of ristocetin are added to the patient’s own platelets and plasma. At the standard doses of ristocetin, the test is not as sensitive as the

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Fig. 2. (A) Manner by which the function of VWF is estimated with the ristocetin cofactor assay using formalin-fixed normal platelets. The slope of the ‘‘agglutination’’ response is proportional to the concentration of VWF. (B) Multimeric analysis of VWF using low (0.65%) concentration agarose. The VWF is detected with a radiolabeled polyclonal antibody to VWF and is visualized by radiography. NP, normal pool plasma; TTP, thrombotic thrombocytopenic purpura; VSD, ventricular septal defect. (Courtesy of R.R. Montgomery, MD, Milwaukee, WI.)

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Fig. 3. Markedly reduced specific activity of VWF:RCo/VWF:Ag in patients who had type 2M VWD. Assays for VWF:RCo and VWF:Ag were performed on 690 persons who had normal VWF multimers and either VWF:Ag or VWF:RCo that was less than 55 U/dL (%). (Courtesy of R.R. Montgomery, MD, Milwaukee, WI.)

VWF:RCo assay to detect abnormal VWF binding and agglutination nor can it be quantitated. At lower doses of ristocetin, the hyperresponsiveness of VWF binding to GP1b can be detected in patients who have type 2B VWD or platelettype VWD. Platelet-rich plasma from patients who have these disorders demonstrates platelet agglutination in the presence of low-dose ristocetin, whereas platelet-rich plasmas from normals and patients who have other VWD variants do not [40,42]. Differentiation of type 2B VWD from platelet type VWD can be performed with an assay that uses frozen patient plasma and formalinfixed platelets (Fig. 4). von Willebrand factor multimers The full range of VWF multimers in plasma is demonstrated best by electrophoresis in low concentration (0.65%) agarose gels in the presence of sodium dodecyl sulfate (imparts negative charge to proteins and results in separation by size). The multimers are stained with radiolabeled antibody to VWF and visualized by autoradiography or luminography (see Fig. 2B) [69,70]. Patients who have types 2A and 2B VWD demonstrate absence of the high (types 2A and 2B) and intermediate (type 2A) molecular weight multimers. All multimers

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Fig. 4. The differentiation of type 2B VWD and platelet-type VWD by the dose-response of ristocetininduced VWF binding to fixed platelets. Type 2B VWD plasma has increased binding. (Courtesy of J.P. Scott, MD, Milwaukee, WI.)

are present in normal plasma and types 1, 2M, and 2N VWD; multimers are undetectable in type 3 VWD. Alteration of VWF multimers also is evident in acquired disorders, such as disseminated intravascular coagulation, and congenital cardiac disorders, such as ventricular septal defect (see Fig. 2B), aortic stenosis, and patent ductus arteriosis [71,72]. Higher than normal molecular weight multimers can be seen in patients who have recurrent thrombotic thrombocytopenic purpura (see Fig. 2B). More precise definition of the satellite bands of VWF can be demonstrated in agarose gels of higher concentration for identification of unusual subtypes of type 2A VWD; however, this technique is not as sensitive for demonstration of abnormalities of the higher molecular weight multimers [73,74]. Factor VIII:C In addition to assays of VWF, FVIII:C also should be evaluated in patients who have VWD to aid in the planning of therapy when baseline FVIII levels are less than normal. If FVIII:C levels are less than VWF:Ag, consideration should be given to the diagnosis of type 2N VWD, in which the VWF binding site for FVIII is abnormal. Assays have been developed in which the patient’s VWF is captured with a monoclonal antibody, the FVIII is removed, and the binding of recombinant FVIII is determined [75]. A decreased affinity of FVIII binding to VWF is the hallmark of type 2N VWD. Pitfalls in the diagnosis of von Willebrand disease Despite advances in diagnostic and molecular biologic techniques, the diagnosis of type 1 VWD remains difficult. This is due to several factors. First, the diagnosis is dependent on a clear cutoff of VWF:RCo and VWF:Ag assays be-

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tween normal and affected individuals. This is a near impossibility for individuals who are affected mildly because VWF levels are influenced by many extragenic factors, such as age, inflammation, stress, pregnancy, hormonal cycles, hypo- or hyperthyroidism, and various medications [76–78]. The effect of stress on children makes the diagnosis particularly difficult because anticipation of phlebotomy may increase VWF levels into the normal range in patients who are affected mildly and repeated evaluations may be needed to make the diagnosis. The stress of vaginal delivery increases VWF levels into the normal range in newborns; this makes the diagnosis difficult in neonates as well [79,80]. Artifacts in plasma VWF quantity, structure, and function may be introduced during the collection and processing of blood samples. For example, residual platelets that are present in samples that have been centrifuged at 1500g for 5 to 10 minutes may be as high as 30,000/mL to 40,000/mL; when the samples are frozen, platelet proteases are released that may alter VWF structure and result in an apparent increase in VWF:Ag and decrease in VWF:RCo. Some laboratories have attempted to filter plasma through 0.2-mm filters, which have adsorbed the high molecular weight multimers of VWF and give the appearance of types 2A or 2B VWD. Difficult phlebotomies may activate the coagulation cascade and cause an apparent increase in FVIII:C activity in PTT-based assays. Therefore, it is imperative that proper drawing and handling of samples be performed to prevent the artifacts that may impair the accurate diagnosis of VWD. Interpretation of the confounding effect of ABO blood group on VWF levels has been the subject of considerable controversy. Because individuals who have blood group O have significantly lower VWF levels than those of other blood groups, some investigators advocated the use of blood group–specific normal ranges to define the cutoff between normal and decreased VWF:Ag and VWF:RCo levels. It is likely that individuals who have VWF levels that are less than the population mean are at increased risk for excessive bleeding, regardless of whether the deficiency is caused by blood group–related increased clearance of VWF or a specific mutation in the VWF gene [29,81]. More definitive studies are needed to define the risk of clinically-significant hemorrhage in individuals who have different levels of VWF concentrations. These data are needed to address whether persons who have mild decreases of VWF should be labeled as having von Willebrand ‘‘disease’’ or if other descriptions should be used [82]. The recent reports of type 1 VWD that was nonlinked to the VWF gene in families who had a diagnosis of VWD [34,83] will raise additional considerations about nomenclature and diagnosis.

Treatment Principles of treatment Of major importance in the consideration of therapeutic options for an individual patient is the establishment of an accurate diagnosis of the severity and

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type of VWD. Because hemostasis testing often is technically difficult, the clinician who relies on an inexperienced laboratory will have great difficulty in the treatment of a patient when the proper diagnosis is masked by laboratory artifact. Therefore, a high-quality and experienced coagulation laboratory should be used. After an accurate diagnosis has been established, replacement therapy and other therapeutic maneuvers can be planned to restore balance to the hemostatic system. For example, if the patient synthesizes normal VWF but the concentration is reduced (hypoproteinemia), the plasma level of VWF generally can be increased by administering desmopressin, a vasopressin analog that promotes release of VWF from storage sites into the circulation. If the patient’s VWF is qualitatively abnormal, mild bleeding may be able to be treated with desmopressin, whereas severe bleeding requires the administration of a replacement product that contains normal VWF and FVIII. One must know the hemostatic level that must be achieved and the half-life of the transfused protein to treat a particular clinical manifestation [84]. Ristocetin cofactor (VWF:RCo) activity is the currently accepted standard assay for measuring VWF activity although it has inherent variability, depending on methodology. This test has been used widely to diagnose and assess the treatment of patients who have VWD [85–89]. Based on treatment practices of hematologists in the United States [90], a FVIII:C and VWF activity (VWF:RCo) level of 40% to 50% is considered sufficient to treat minor bleeding, such as epistaxis, menorrhagia, lacerations, tooth extractions, and minor surgery. For major surgery or life-threatening hemorrhage, an initial level of 80% to 100% is desired; thereafter, VWF should be maintained at greater than 50% for at least 3 days, but FVIII should be maintained at greater than 50% for 5 to 7 days and greater than 30% for an additional 5 to 7 days as recommended for treatment of hemophilia A to prevent late bleeding [91,92]. If the patient’s response to desmopressin is known to result in hemostatic levels, then desmopressin is the treatment of choice; if not, replacement therapy with VWF/FVIII concentrates must be undertaken. If replacement therapy is required, FVIII and VWF replacement must be considered. Based on the volume of distribution of VWF and the quality of the VWF multimers in plasma-derived concentrate, a dose of 1.0 to 1.5 ristocetin cofactor units/kg body weight will increase the plasma VWF level by 2% and 1.0 FVIII:C units/kg body weight will increase the plasma FVIII level by 2% [92]. Therefore, one must know the VWF:RCo and FVIII:C content of the product to be used when calculating replacement doses. Finally, knowledge of the half-life of VWF (approximately 12 hours) and FVIII:C (increases to about 18 hours during treatment with VWF concentrate) is important when replacement therapy is extended beyond the initial infusion. Treatment products Desmopressin Desmopressin (1-desamino-8-D-arginine vasopressin), a synthetic vasopressin analog, increases FVIII and VWF levels and allows successful dental and surgical

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treatment of patients who have VWD [93–96]. Desmopressin is considered to be the treatment of choice in those who respond to the drug because of its safety from the risk of transfusion-transmitted viral infections. The individual response to desmopressin is variable [97] and the half-life of released VWF may vary as well [98]. Thus, most clinicians recommend a trial dose with laboratory measurement of the VWF:RCo response (and FVIII if baseline levels are abnormal) before desmopressin is used for the treatment of bleeding episodes and prophylaxis for dental and other surgical procedures [99,100]. Usually, an individual responds similarly with repeated doses [101]; thus, the plasma level of VWF:RCo in response to a trial dose of desmopressin can be used to predict responses for the design of future therapy. For example, a patient who has VWD who achieves a 40% VWF:RCo level after desmopressin stimulation should be treated with desmopressin for tooth extractions and minor surgical procedures; however, desmopressin would not be sufficient for treatment of life-threatening hemorrhages or in preparation for major surgery—situations in which an 80% to 100% level is indicated. Desmopressin is available in an intravenous (IV) form and a concentrated intranasal form (Stimate) [102–104]. Care must be taken to ensure that pharmacists do not substitute the dilute intranasal preparation (brand name: DDAVP), which is formulated for the treatment of enuresis and diabetes insipidus; it is not effective for treatment of VWD. The recommended dose of IV desmopressin is 0.3 mcg/kg body weight [94,97] which is diluted in 25 to 50 mL normal saline and administered over 30 minutes. The dose of intranasal desmopressin is 150 mcg (one puff) for patients who weigh less than 50 kg and 300 mcg (two puffs) for those who weigh at least 50 kg. Because the maximal increase in VWF/FVIII occurs at 30 to 60 minutes, it is advisable to time the infusion as close as possible to the surgical procedure. Tachyphylaxis may occur with repeated doses of desmopressin and varies from patient to patient [105]. Therefore, if repeated dosing is contemplated for major surgery or life-threatening hemorrhage, VWF:RCo and FVIII:C levels should be monitored and replacement therapy initiated as needed. In general, if 2 days have elapsed between doses, response similar to baseline can be expected. Usually, side effects are minimal and include facial flushing, headache, or mild increases in pulse rate or blood pressure that resolve when the infusion is slowed or discontinued. Rare cases of seizures and central nervous system injury that are associated with hyponatremia have been reported [106–108]. Therefore, fluids must be restricted to no more than maintenance for at least 24 hours following any dose of desmopressin and serum sodium levels should be monitored in the patient who is treated with repeated doses; generally, hyponatremia responds to more stringent fluid restriction. If scrupulous attention is paid to fluid balance, including written instructions to patients/parents when the drug is given in the outpatient setting, desmopressin can be administered safely to small children [100,104]. Thrombosis has occurred rarely [109] so the drug should be used with caution in patients who are at increased risk.

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von Willebrand factor/factor VIII concentrates For patients who do not respond to desmopressin, replacement therapy with products that contain normal VWF and FVIII are indicated. Several commercial plasma-derived FVIII concentrates are available, although only one, Humate-P (contains more intact VWF multimers), is licensed by the U.S. Food and Drug Administration for use in patients who have VWD [85,86,88]. These VWF/FVIII concentrates have been used widely with success for treatment of bleeding episodes and surgical prophylaxis [85–88,90,110]. The ratio of VWF:RCo to FVIII:C varies widely from 2:1 to 0.5:1 in the products that are available, presumably as a result of the differences in degradation of high molecular weight multimers during processing. Thus, there is as much as a fourfold difference in FVIII:C per unit of VWF:RCo from product to product; these differences, in addition to the specific patient’s baseline levels of both proteins, must be taken into account in calculating replacement doses for various treatment settings. Although transfusion-related elevated FVIII:C levels have not been proven to increase the risk of thrombosis as was seen in nontransfused patients who had elevated FVIII [111], thrombosis was reported with the use of concentrates that contained VWF and FVIII [87,112]. Most of the reported cases were associated with other risk factors for thrombosis, but several patients had extremely high FVIII:C levels during replacement therapy with these concentrates. Therefore, it is prudent to monitor FVIII:C and VWF:RCo during extended replacement therapy to ensure adequate hemostatic levels of both proteins and to avoid the potential risk of thrombosis that is associated with supranormal levels of FVIII:C. The VWF/FVIII products are viral attenuated so risk of transfusiontransmitted viral infection with HIV and hepatitis C virtually has been eliminated. The risk of hepatitis A and B transmission can be reduced further by scrupulous immunization of all patients with the hepatitis A and B vaccines [113,114]. Cryoprecipitate also contains normal VWF and FVIII but is no longer indicated for use in VWD unless other products are unavailable because of the increased risk of viral transmission because of the reliance on screening alone for viral safety. Antifibrinolytic therapy Antifibrinolytic therapy is a useful adjunct, particularly for treatment of injuries that involve the oral and nasal mucous membranes. It is not effective in obtaining initial hemostasis, but prevents rapid clot lysis after hemostasis has been achieved by desmopressin, replacement therapy, or local measures. For example, in the treatment of dental extractions, local control of hemostasis with avatine or fibrin glue with or without a single dose of desmopressin or VWF/ FVIII concentrate usually is sufficient to maintain hemostasis if antifibrinolytic therapy is given until healing is complete [115–117]. Two antifibrinolytic agents are in general use, -aminocaproic acid (EACA; Amicar) and tranexamic acid (Cyclokapron), although tranexamic acid is not available in the United States. EACA is formulated in an oral tablet and an oral elixir form. The tablet is a large 500-mg size and with the usual adult dose of 3 g

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(six capsules), even adults prefer the elixir (1.5 g/5 mL). The oral dose of EACA is 100 mg/kg (maximum 6 g) initial dose followed by 50 mg/kg (maximum 3 g) every 6 hours. Tranexamic acid also is available in 500-mg capsules but they are smaller and the smaller recommended oral dose (25 mg/kg every 6–8 hours) is more tolerable. Both can be used as a mouthwash for oral mucous membrane injuries or tooth extractions to avoid systemic side effects [118]. The Amicar injectable formulation (1.5 g/5 mL) used as a mouthwash is effective (and considerably less expensive) at a dosage of 10 mL every 6 hours; the patient is instructed to swish the Amicar over the extraction site for 2 minutes and then expectorate. von Willebrand disease type-specific treatment considerations Treatment of VWD depends on the type of VWF defect and on the patient’s response to desmopressin. Treatment products that are appropriate for each type are summarized in Table 2. The most common quantitative defect in VWD, a functional molecule that is present in decreased amounts, is found in patients who have type 1 VWD. Most of these patients respond to administration of desmopressin with a three-fold to fivefold increase in plasma VWF [94–97,104,105]. Generally, a single dose of desmopressin is sufficient for minor bleeding and tooth extractions. For oral bleeding and tooth extractions, antifibrinolytic therapy also is recommended. It is advisable to perform a desmopressin trial to determine the individual response before its use for a major surgical procedure; in general, if the VWF activity (VWF:RCo) increases to greater than 100% (IU/dL) the patient can be treated with desmopressin alone. For major surgery, dosages that are given every 12 to 24 hours for 2 to 3 days postoperatively usually are sufficient to maintain hemostatic levels of VWF are greater than 40% to 50%. In patients who have decreased baseline VWF:RCo, levels should be measured daily and exogenous VWF/FVIII concentrate should be administered if tachyphylaxis occurs. In patients in whom FVIII:C levels also are decreased, FVIII:C should be monitored and maintained at a hemostatic level as recommended for hemophilia A. In patients who have qualitative defects, the specific VWF defect must be considered in planning rational therapy. For those who have type 2A VWD that is caused by increased proteolysis of VWD, administration of desmopressin may result in transient increases of VWF:RCo into the hemostatic range to allow for treatment of minor bleeding, tooth extractions, and minor surgery. For major bleeds and surgery, replacement therapy with VWF/FVIII concentrate usually is required. Minor bleeding in type 2M VWD also may be treatable with desmopressin; however, for major bleeding or surgery, replacement therapy should be given. Patients who have type 2B VWD or platelet-type VWD may have thrombocytopenia that is exacerbated by the administration of desmopressin. Therefore, desmopressin generally is considered to be contraindicated in this group, although some investigators believe that it is useful for some patients, particularly

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VWD type

Desmopressin

VWF/FVIII concentrate

Platelets

1

Treatment of choice if trial dose results in therapeutic hemostatic levels May result in transient responses useful for minor bleeds and procedures May cause further decrease in platelet count

If desmopressin is not effective or if higher levels are required Required for major bleeding and surgery

Not indicated

Required for major bleeding and surgery

Indicated if thrombocytopenia remains severe after VWF replacement Initial treatment of choice Not indicated

2A 2B Platelet-type 2M 2N 3

May cause further decrease in platelet count May result in partial responses useful for minor bleeds and procedures May result in partial, but transient, responses useful for minor bleeds and procedures Not indicated

May cause further decrease in platelet count Usually required for major bleeding and surgery Usually required for major bleeding and surgery; highly purified FVIII concentrate not effective Required for major bleeding and surgery

Not indicated

Not indicated Not indicated unless bleeding persists despite adequate plasma VWF/FVIII levels

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Table 2 Treatment alternatives for von Willebrand disease

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for minor bleeding [109,119,120]. Replacement therapy with VWF/FVIII concentrate is required for treatment of major bleeds and surgery in type 2B VWD; platelets may need to be given if thrombocytopenia is severe, but normal VWF– containing concentrates should be given first. For patients who have platelet-type VWD, platelet transfusion is indicated for treatment of hemorrhages; rarely, VWF replacement also is needed. In type 2N VWD, there is a decreased binding affinity of FVIII to VWF, which results in accelerated clearance of the unbound FVIII. Because symptomatic patients are homozygotes or compound heterozygotes, the administration of desmopressin has only a transient effect on FVIII levels. Similarly, administration of a highly-purified recombinant or monoclonal purified-FVIII concentrate would result in rapid clearance of FVIII with only transient benefit. Therefore, for major bleeding or surgical prophylaxis, a concentrate that contains normal VWF is required.

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