von Willebrand disease should be suspected in any patient with mucocutaneous bleeding despite a normal platelet count. The symptoms may be highly variable with time in a single patient, and all affected members of a given pedigree may not have the same difficulty with bleeding.73,169– 171 Even for severely affected patients with symptoms since birth and a clear family history, the pattern of bleeding is not specific for von Willebrand disease. Thus, final diagnosis depends on laboratory testing and may require repeated examinations of patients and family members.
Detailed reviews of the laboratory assessment of VWD can be found elsewhere.172,173 Tests commonly applied to the diagnosis of VWD fall into four general categories:
The template bleeding time. This test assesses the formation of the platelet plug in vivo by determining the time required to stop bleeding from a standard skin laceration. It is difficult to standardize, and consistent results depend strongly upon the skill of the tester. A prolonged bleeding time is not at all specific for VWD because connective tissue and platelet disorders may also exhibit this abnormality. Patients with mild VWD intermittently may have normal bleeding times.73
Platelet aggregation stimulated by the antibiotic ristocetin. This test measures VWF binding to platelet GPIb. Two variations are used. One (ristocetin-induced platelet aggregation [RIPA]) employs patient platelets suspended in autologous plasma. The second (ristocetin cofactor activity) employs patient plasma with washed and fixed allogeneic platelets. In each assay, platelet aggregation as a function of ristocetin concentration is compared to normal controls, and the concentration required to achieve a specific degree or rate of aggregation is noted. The snake-venom factor botrocetin has effects similar, but not identical, to those of ristocetin, and can also be used to measure the ability of VWF to bind to resting platelets.174,175
Measurement of factor VIII antigen or activity in patient plasma. Factor VIII binds to plasma VWF, so that factor VIII levels usually reflect VWF antigen concentration. Comparison of ristocetin cofactor activity with factor VIII level provides an estimate of the specific activity of the residual VWF protein in patient plasma. This ratio of ristocetin cofactor activity to factor VIII level is expected to be normal for quantitative deficiencies of VWF and reduced for variants of VWD with a qualitatively abnormal protein.
Physical characterization of patient VWF. Gel electrophoresis and immunochemical assays measure VWF concentration, as well as multimer distribution. This category of assays includes the quantitative immunoassay of VWF antigen and the qualitative assessment of multimer distribution by counterimmunoelectrophoresis. More precise assessment of multimer distribution is obtained by electrophoresis of plasma on agarose or agarose/acrylamide copolymer gels in the presence of sodium dodecyl sulfate (Fig. 174-4). In such systems, the VWF multimers are separated according to size and can be visualized by reaction with 125I-labeled antihuman VWF antibody and autoradiography53,54 or by immunoenzymatic methods.
Multimer patterns in variants of von Willebrand disease. Plasma VWF multimers in type 1 VWD have mobility similar to those from normal controls (N). Larger multimers are missing in VWD type 2A (lanes 3 and 5) and type 2B (lane 4). No multimers are visualized in VWD type 3 (lane 6). (Adapted from Sadler.289 Used by permission.)
Comparison of platelet and plasma VWF with these assays may be useful in the further characterization of specific variants of VWD.176,177 In addition, the time course of response of plasma factor VIII, VWF antigen, ristocetin cofactor activity, and VWF multimer structure to a trial infusion of the vasopressin analogue DDAVP can distinguish still more phenotypic heterogeneity.177– 179 Assays of VWF binding to collagen, heparin, or factor VIII also have been described, but are less widely available. Finally, the detailed investigation of family members to show inheritance of VWD is useful to firmly exclude acquired conditions that may mimic VWD.
von Willebrand disease appears to be the most common inherited bleeding disorder of human beings, but the prevalence is difficult to determine precisely because of substantial variation in the severity of disease. If all cases that come to the attention of specialized referral centers are included, the prevalence of symptomatic VWD in Sweden is approximately 125 per million population.180 However, the screening of an unselected population of schoolchildren in Italy suggests that the prevalence of inherited VWF abnormalities is much higher, ≈8000 per million population.76 Severe VWD with essentially no detectable circulating VWF antigen is quite rare and affects 0.5 to 3 per million population in Western Europe and Scandinavia,181 and perhaps as many as 5.3 per million population among selected Arab populations in the Middle East.182
The genetics of VWD illustrate some of the problems in the use of the terms dominant and recessive to describe human phenotypes (see Chap. 1). In many families, heterozygosity is consistently associated with obvious phenotypic effects and the dominant description is satisfactory. In other instances, heterozygosity is relatively or totally asymptomatic and may be associated with subtle laboratory abnormalities, thus blurring the separation of dominant and recessive phenotypes. In addition, it is likely that the genotype at other loci and nongenetic factors influence the phenotype, particularly in individuals heterozygous for VWD. Recognizing these limitations, it is still useful to separate phenotypes generally as dominant or recessive disorders.
In most pedigrees, VWD is transmitted as an autosomal dominant trait. By contrast, many patients with severe VWD who appear to be homozygotes or compound heterozygotes for a mutant allele at the VWF locus are born to clinically normal parents. Sensitive testing may disclose mild functional abnormalities in such parents who are obligate heterozygotes, but these families are usually considered affected by a recessive disease. Selected pedigrees may exhibit both dominant and recessive patterns of inheritance.1,170,171 This variability suggests that some interplay between specific mutant alleles and the genetic background of the host determines whether clinically significant bleeding may occur. Certain variants of type 2 VWD consistently exhibit recessive inheritance although most are dominant.
One unlinked modifier of plasma VWF levels appears to be related to ABO blood type. Both VWF antigen74,75 and ristocetin cofactor activity76 are lower in persons of blood type O compared to blood types A and B.
Classification and Molecular Defect
The current classification of VWD is based on pathophysiological mechanism.183 The correspondence with previous classifications is straightforward.183 VWD is divided into three broad categories based on whether the VWF in blood plasma is qualitatively normal (type 1), abnormal (type 2), or absent (type 3). These categories correlate fairly well with the VWF multimer pattern observed in plasma. In type 1 VWD, all normal multimer species are present but reduced proportionally; assays of VWF antigen and function also are reduced proportionally. This pattern suggests a simple quantitative deficiency of VWF. In type 2 VWD, the plasma VWF exhibits defective structure or function, indicating a qualitative abnormality of the protein. In some such variants, the larger VWF multimers are absent (Fig. 174-4). Further subdivision of type 2 VWD is made based on the response of patient VWF to ristocetin, on the VWF multimer structure, and on the affinity of VWF for factor VIII. A third category, type 3 VWD, is distinguished by the virtual absence of VWF antigen and activity from plasma, and by clinically recessive inheritance. This scheme has the advantage that the major subdivisions identify patient groups having distinctive biochemical and clinical characteristics.
In principle, deficiency of VWF activity could result from lesions within the VWF gene or indirectly as a consequence of mutations that affect biosynthesis or metabolism. No cause of human VWD that is unlinked to the VWF locus has been described to date.
This chapter emphasizes the properties of VWD types for which molecular defects are defined (Table 174-2). A database of VWD mutations with comprehensive references has been published.184 An updated version is maintained by David Ginsburg at the University of Michigan and is accessible online at http://www.medgen.med.umich.edu/labs/ginsburg/intestframe.html. A catalogue of most known variants of VWD was compiled by Zaverio Ruggeri;185 that review and selected more recent publications186,187 can be consulted for references to case reports for rare or unclassified variants.
Table 174-2: Classification of von Willebrand Disease |Favorite Table|Download (.pdf) Table 174-2: Classification of von Willebrand Disease
|Von Willebrand Disease ||Genetics ||Factor VIII ||VWF Antigen ||Ristocetin Cofactor Activity ||RIPA ||Multimer Structure |
|Type 1 ||Dominant ||Decreased ||Decreased ||Decreased ||Decreased ||Normal in plasma and platelets |
|Type2A ||Dominant (usually) ||Decreased or normal ||Decreased or normal ||Decreased relative to antigen ||Decreased relative to antigen ||Large and intermediate multimers absent from plasma; variable in platelets |
|Type 2B ||Dominant ||Decreased or normal ||Decreased or normal ||Decreased or normal ||Increased ||Large and intermediate multimers absent from plasma; normal in platelets |
|Type 2M ||Dominant (usually) ||Decreased or normal ||Decreased or normal ||Decreased relative to antigen ||Decreased relative to antigen ||Large and intermidiate multimers present in plasma and platelets |
|Type 2N ||Recessive ||Moderately to markedly decreased ||Normal ||Normal ||Normal ||Normal in plasma and platelets |
|Type 3 ||Recessive ||Moderately to markedly decreased ||Absent or trace ||Absent ||Absent ||None or trace in plasma or platelets |
Type 1 Von Willebrand Disease.
VWD type 1 is the most common form of VWD and accounts for approximately 70 percent of cases seen in specialized treatment centers.180,188 Plasma VWF is reduced; ristocetin cofactor activity and factor VIII usually are reduced proportionately, and the multimer distribution is normal. This is compatible with a simple quantitative deficiency of VWF with no intrinsic functional abnormality. Inheritance is usually autosomal dominant.
VWD type 1 is a heterogeneous disorder. Patients in some pedigrees have a normal content of platelet VWF, while in other families the patients have similar deficiencies of both plasma and platelet VWF.176,177 These distinctions may correlate with the efficacy of therapy with DDAVP.177 The mutations in VWD type 1 that have been characterized so far mainly consist of nonsense mutations, frameshifts, and deletions that also are found in VWD type 3.189– 191
A few families are affected by VWD type 1 that is inherited with high penetrance and characterized by exceptionally low VWF levels. VWF is multimeric, and mutations that interfered with multimer synthesis or secretion could explain such a strongly dominant phenotype. In one family, the missense mutation C386mR (see mutation nomenclature note under “Type 2 von Willebrand disease” below) was shown to reduce the secretion of coexpressed normal VWF subunits, probably by causing the retention of heterodimers in the endoplasmic reticulum. This dominant-negative mechanism may explain some unexpectedly severe VWD type 1 phenotypes.192
A normal-appearing multimer distribution does not correlate perfectly with normal function. Because type 1 VWD is constrained to include only quantitative disorders, some variants previously designated as type 1 were reclassified under type 2, mainly as type 2M.
Type 2 Von Willebrand Disease.
Type 2 VWD includes all variants in which the circulating protein is qualitatively abnormal, with a defect in stability, function, or multimer distribution. Additional subdivision of type 2 VWD is made on the nature of the functional defect and analysis of VWF multimer patterns (Fig. 174-4).
Type 2a Von Willebrand Disease.
In type 2A VWD, both ristocetin-induced platelet aggregation and ristocetin cofactor activity are disproportionately decreased relative to VWF antigen, indicating that the residual plasma VWF has reduced function.54 Large and intermediate plasma VWF multimers are absent, and the smallest multimer may be relatively increased. This subgroup is heterogeneous: the plasma VWF levels may be normal or decreased, and the distribution of platelet VWF multimers is variable.54,176 In some patients, the plasma and platelet multimers exhibit similar decreases in large multimers that suggest a defect in polymerization. In other patients, the platelet multimer distribution appears normal, and increased sensitivity to proteolysis may contribute to the abnormal plasma VWF multimer distribution.193,194 This heterogeneity is supported by the variable response to DDAVP in VWD type 2A. Some patients show at least a partial correction of both bleeding time and multimer distribution after treatment with DDAVP; others consistently fail to respond.179,194,195 The mode of inheritance usually is dominant, and this variant accounts for approximately three-fourths of all type 2 VWD.
Several missense mutations that cause dominant type 2A VWD have been characterized, most of which are within VWF domain A2 (Fig. 174-5).184 As was predicted from the phenotypic variability of type 2A VWD, these mutations can be divided into two groups that appear to cause similarly abnormal plasma VWF multimer patterns by distinct mechanisms.196 One group includes the mutations V844mD, S743mL, and G742mR. (Missense mutations are designated in single-letter code with the normal amino acid followed by the number of the position, which is followed by the mutant amino acid. Positions in the prepro region are numbered by codon number and are indicated by subscript p. Positions in the mature subunit are numbered from the first residue of the mature subunit, which corresponds to codon 764, and are indicated by subscript m (e.g. V844mD is Val at position 844 in the mature subunit mutated to Asp).) These particular mutations were shown to impair the assembly and secretion of normal VWF multimers, and patients with these mutations have decreased large VWF multimers in both plasma and platelets. The second group includes the mutations R834mW and G742mE, which are compatible with the synthesis and secretion of normal appearing VWF multimers. Patients with these mutations have normal platelet VWF multimer patterns, and the deficiency of plasma VWF multimers apparently is caused by increased proteolytic degradation in the circulation.196 For some patients with type 2A VWD, a major site of proteolytic cleavage in the VWF subunit was shown to be the Tyr842m-Met843m bond.197 A metalloprotease recently was partially purified from plasma that can cleave this bond.198,199 The dominant variant originally described as type IID206,207 is caused by mutations in the CK domain that prevent the formation of proVWF dimers within the endoplasmic reticulum. The mutant proVWF monomers are transported to the Golgi where they form nonfunctional “head-to-head” dimers.208
Mutations in VWD type 2. References to the individual mutations can be found in the database of VWD mutations184 maintained at the University of Michigan and accessible at http://www.medgen.med.umich.edu/labs/ginsburg/intestframe.html.
Recessive forms of VWD type 2A have been described. The variant originally designated VWD type IIC200– 204 is caused by mutations in the propeptide that impair multimer assembly in the Golgi apparatus, probably by interfering with the normal function of the propeptide in promoting intersubunit disulfide bond formation.205 The recessive and dominant type 2A variants share a common pathophysiologic mechanism in which the lack of large VWF multimers prevents effective VWF-dependent platelet adhesion.
Several other rare type 2 variants are included under VWD type 2A. In general, these loss of function variants were defined initially by unique features of individual multimers upon high-resolution gel electrophoresis. These include the former type IIE,85 type IIF,209 type IIG,210 type IIH,211 and type II-I.187 The latter four types represent single case reports.
Type 2b Von Willebrand Disease.
Type 2B VWD includes variants in which the mutant VWF has increased affinity for platelet GPIb. Laboratory testing shows hyperresponsiveness of platelet-rich plasma to ristocetin in the RIPA assay,212 although ristocetin cofactor activity may be decreased or normal. Plasma VWF multimers usually show a decrease in large multimers, but platelets contain a normal multimer distribution.54 Administration of DDAVP to patients with type 2B VWD causes the release of large multimers into the circulation, but the larger species are rapidly cleared, apparently through spontaneous binding to platelet GPIb. The binding of mutant VWF to platelets is accompanied by transient thrombocytopenia that can be severe.213 Thus, the small multimer pattern in this variant is at least partly due to enhanced clearance of large multimers rather than to a polymerization defect. The increased RIPA is due to the presence of large, abnormal, hyperresponsive VWF multimers adsorbed to patient platelets in platelet-rich plasma. The normal or decreased ristocetin cofactor activity is due to the absence of these same multimers from (platelet-poor) patient plasma, so that added allogeneic platelets are not agglutinated by them. Variants of this subtype have been reported with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation in vitro.214,215 The disorder is transmitted as a dominant trait; a few families with de novo mutations have been reported.184,216,217 The few cases described of normal multimer distribution with hyperresponsiveness to ristocetin218,219 appear to represent a mild form of type 2B defect. Type 2B VWD appears to account for less than 20 percent of all type 2 VWD.
Mutations that cause VWD type 2B (Fig. 174-5)184 cluster within a spatially restricted region of VWF domain A.149,150 This cluster may mark the location of a regulatory site that normally inhibits the binding of domain A1 to platelet GPIb. Mutations within this region appear to relieve this inhibition and cause the observed dominant gain-of-function phenotype.
Type 2m Von Willebrand Disease.
Type 2M (for “multimer”) refers to variants with decreased platelet-dependent function that is not caused by the absence of large VWF multimers.183 Despite the normal sized multimers, the presence of a functional defect indicates that the multimers must contain qualitatively abnormal VWF subunits. Type 2M includes variants with normal multimer distribution but decreased ristocetin cofactor activity,220,221 the presence of large amounts of uncleaved proVWF in the multimers,222 or larger than normal plasma multimers.223 Such variants often were classified previously as distinct forms of VWD “type I.”
One mechanism that causes VWD type 2M is decreased binding affinity for platelet GPIb due to mutations in VWF domain A1, and several patients with normal VWF multimer distributions have had mutations in the Cys509m-Cys695m disulfide loop of domain A1 that prevented binding to GPIb. These mutations include deletion of the segment R629m-Q639m,224 and the missense mutations F606mI,225 I662mF,225 and G561mS226 .
Type 2n Von Willebrand Disease.
An interesting variant of type 2 VWD is characterized by factor VIII deficiency that is caused indirectly by mutations in VWF.227,228 The abnormal VWF does not bind to factor VIII and consequently does not stabilize it in the circulation; otherwise it apparently is normal, with normal levels of VWF antigen, normal indices of platelet-dependent VWF function such as bleeding time and ristocetin cofactor activity, and normal VWF multimer distribution. Thus, this type 2 VWD variant mimics hemophilia A except that the pattern of inheritance is autosomal recessive rather than X-linked recessive. This phenotype was named VWD type 2N after Normandy, the birth province of one proband.228
In one affected family, a male patient with VWD type 2N was misdiagnosed with hemophilia A, and moderate factor VIII deficiency in a sister was incorrectly attributed to extreme lyonization in a carrier of hemophilia A.229 The prevalence of VWD type 2N is not known precisely, but screening of clinic patients suggests that a few percent of patients with apparent mild hemophilia A actually have VWD type 2N.230 This diagnosis should be considered in patients with congenital factor VIII deficiency in whom the disorder is not clearly X-linked, because correct diagnosis has important implications for therapy and genetic counseling.229
Several mutations causing VWD type 2N have been identified within the factor VIII binding domain of VWF (Fig. 174-5).184 In some patients, defects in factor VIII binding are associated with symptomatic decreases in platelet-dependent VWF functions. Such intermediate phenotypes can be caused by coinheritance of VWD type 1 and type 2N alleles,231 and indicate that compound heterozygosity can strongly influence the clinical presentation of VWD variants.
Type 3 Von Willebrand Disease.
Patients with type 3 VWD have essentially no detectable VWF antigen or activity in blood plasma, and usually have factor VIII levels <10 percent of normal.25,232,233 These patients appear to have received two defective VWF alleles, and many have clinically unaffected parents.
Because the prevalence of recessive type 3 VWD (q2) is ≈0.5 to 3 per million population, heterozygotes (2pq) should comprise at least 1400 to 3500 per million population; however, the prevalence of symptomatic type 1 VWD appears to be at least tenfold lower. Clearly, most heterozygous relatives of patients with type 3 VWD are not symptomatic. There is variability in expression among heterozygotes within families that contain type 3 VWD patients, and deficiencies of VWF antigen and ristocetin cofactor activity can often be detected in clinically normal relatives.170,171
Patients with VWD type 3 usually are compound heterozygous for VWF alleles with frameshifts, large deletions, or nonsense mutations; homozygosity has been demonstrated in a few consanguineous families.184,189,190,191 The mutation in the original von Willebrand family is a single nucleotide insertion in exon 18 that causes a frameshift and premature termination within the propeptide.234 Large deletions in the VWF gene predispose patients with VWD type 3 to the development of inhibitors during therapy. A similar correlation has been noted for hemophilia B and deletions of the factor IX gene235 (see Chap. 173).
For patients with a quantitative deficiency of VWF (VWD types 1 and 3) the severity of disease generally correlates with the degree of VWF functional deficiency, and may vary from clinically insignificant to life threatening. The severity of the disease in patients with qualitative disorders of VWF (VWD type 2) may exceed what might be expected based on the functional deficiency ascertained by laboratory tests.201,203,206,209 Symptoms are usually present from childhood, and often from birth.7,8,10,25 These commonly include easy bruising, cutaneous hematomas, epistaxis, bleeding from gums, and prolonged bleeding from cuts. Persistent severe bleeding after minor oral trauma and after dental extraction is common. Most affected women have menorrhagia that may require blood transfusion.169 Bleeding from a ruptured ovarian follicle or corpus luteum may also be severe.180,203 Gastrointestinal bleeding seems to be relatively rare but may be life threatening. Patients with VWD type 3 and essentially undetectable VWF can have factor VIII levels low enough to predispose to spontaneous hemarthrosis, joint deformities, and soft tissue bleeding.7,8,25 Milder forms of VWD are almost never associated with hemarthrosis. The bleeding tendency of VWD has been reported to decrease with advancing age,7,25 although this is not a uniform feature of the disease.
During pregnancy the plasma VWF levels are increased in normal individuals and in patients with most forms of VWD other than VWD type 3.236– 239 This increase is most marked in the third trimester. If the increase represents functional VWF, then labor and delivery are usually uncomplicated. Patients with dysfunctional VWF (VWD type 2) frequently have difficulty with hemorrhage during labor and delivery.201,206,219 Plasma VWF levels return to baseline within a few days, and patients with VWD should be watched closely during at least the first week after delivery for postpartum bleeding.
Type 2B VWD can present special problems during pregnancy. The increased plasma concentration of abnormal VWF that is a consequence of the physiological stimulus of pregnancy can cause severe and prolonged thrombocytopenia, rarely with marked blood loss during delivery.240 Children born with VWD type 2B may present with congenital thrombocytopenia.217
The development of alloantibodies to VWF is distinctly uncommon in VWD as reviewed elsewhere.241 All of the reported cases have occurred in patients with VWD type 3 with no detectable VWF-like protein. Among patients with VWD type 3, the prevalence of alloantibodies to VWF is about 7.5 percent. Not all severely affected patients develop antibodies, and there may be a familial predisposition to this complication of therapy. The apparent association between deletions within the VWF gene and the development of such antibodies was discussed above.
The symptoms that occur in VWD are not specific, and many conditions of quite different pathogenesis may be associated with a similar bleeding diathesis. These include primary platelet disorders, such as Bernard-Soulier syndrome, and the ingestion of antiplatelet drugs. In particular, the use of aspirin by patients with hemophilia A can produce a clinical picture quite similar to severe VWD.242 In most cases, VWD can be excluded easily by appropriate laboratory testing.
VWD type 2B can cause thrombocytopenia that may be confused with idiopathic thrombocytopenic purpura. Such patients who present during pregnancy have received unnecessary therapy with prednisone240,243 or intravenous γ-globulin,244,245 while appropriate therapy with factor VIII concentrates was withheld. Two men, who were ultimately found to have VWD type 2B, underwent splenectomy for presumed idiopathic thrombocytopenic purpura unresponsive to prednisone.214,246 This subtype of VWD also is associated with postoperative thrombocytopenia,247 and has presented as congenital thrombocytopenia.217
Two conditions are especially difficult to distinguish from VWD because they may cause low VWF levels and abnormal VWF multimer distributions. These are the acquired von Willebrand syndrome and “platelet-type,” or “pseudo,” VWD. The acquired von Willebrand syndrome refers to a condition of spontaneous bleeding associated with decreased VWF occurring in adults without a prior personal or family history of VWD as reviewed elsewhere.241 Most have been associated with a recognized autoimmune or lymphoproliferative disorder that suggests an immunologic cause. Some patients have lacked such underlying diseases, and fewer than half of the afflicted patients were shown to possess autoantibodies to VWF. The multimer distribution in plasma may be normal, or the largest multimers may be absent. In the latter case, discrimination between VWD type 2A and the acquired von Willebrand syndrome may be difficult. Both conditions may be characterized by relatively normal platelet VWF structure and concentration, and by shortened survival in the circulation of the endogenous VWF released by DDAVP. In contrast to VWD type 2A, the ristocetin sensitivity of platelet VWF is normal in the acquired von Willebrand syndrome, and exogenous VWF administered by transfusion has shortened survival.
Platelet-type or pseudo-VWD is clinically very similar to VWD type 2B, but the abnormality lies with the platelet rather than with the VWF.248– 250 The condition is inherited as an autosomal dominant trait. Symptoms resemble those of moderately severe VWD, and laboratory abnormalities include a prolonged bleeding time, decreased plasma VWF and factor VIII levels, increased ristocetin-induced platelet aggregation, absence of larger multimers from plasma, and presence of all multimers in platelets. The effect of DDAVP is like that in VWD type 2B, with transient thrombocytopenia and spontaneous platelet aggregation.251 In contrast to VWD type 2B, the addition of normal plasma, hemophilic plasma, cryoprecipitate, or purified VWF to platelet-rich plasma in this disorder causes platelet aggregation without the addition of ristocetin.249,250,252 Mutations within the gene for platelet GPIba were found in two patients with this disorder: G233V253 and M239V (see Chap. 177).254
Patients with severe VWD may bleed either because they lack sufficient VWF to support normal platelet function or because they are factor VIII-deficient, and the response to therapy in VWD emphasizes the distinct functions of these molecules in hemostasis. Hemarthroses, soft tissue hematomas, and postoperative bleeding usually respond to raising the level of factor VIII, whereas mucocutaneous bleeding responds to infusions of functional VWF.
Factor VIII levels are usually easy to support because even limited amounts of small VWF multimers can stabilize and cause a prolonged elevation of plasma factor VIII level. Correction of the platelet adhesion abnormality is more difficult. Fresh frozen plasma and cryoprecipitate consistently contain functional VWF multimers. The large volume of fresh frozen plasma that is needed to infuse sufficient VWF limits its utility. Cryoprecipitate may shorten the bleeding time in VWD, but the possible transmission of disease by cryoprecipitate makes it less than an ideal therapy. Several virucidally treated factor VIII concentrates that are used for the treatment of hemophilia A contain functional VWF multimers and appear to be effective.255– 257 These currently are the products of choice for the treatment or prevention of serious bleeding in VWD.
A very high purity VWF concentrate that contains little factor VIII was effective in several types of VWD.258– 260 The infused pure VWF binds and stabilizes endogenously synthesized factor VIII, so that factor VIII levels rise in a delayed fashion and peak levels are achieved only after many hours. Recombinant VWF has undergone therapeutic testing in animal models including VWF-deficient dogs.261
The highly purified “monoclonal” or recombinant factor VIII preparations commonly used for the treatment of hemophilia A are inappropriate for almost all patients with VWD because they do not treat the deficiency of functional VWF. In addition, the factor VIII in these products cannot be stabilized effectively by endogenous VWF in patients with VWD type 3 or type 2N.256,262
Platelet transfusions shorten the bleeding time in some VWD patients who are refractory to treatment with factor VIII-VWF concentrates. This effect may reflect the participation of both platelet and plasma VWF in hemostasis.263– 265
Many patients with mild VWD can avoid exposure to blood products through the pharmacologic manipulation of plasma VWF levels. In many patients, the vasopressin analogue DDAVP administered intravenously, subcutaneously, or intranasally causes a three- to sixfold elevation of VWF and factor VIII levels that is maximal in 30 to 90 min.266,267 Levels decrease to baseline over several hours to several days. Repeated doses often elicit a diminished response, but tachyphylaxis is not consistently observed and the efficacy of repeated doses should be evaluated in individual patients as indicated.268,269 For therapy with DDAVP to be effective, the patient must be able to synthesize at least a partially functional VWF. Consequently, DDAVP is expected to be most useful in VWD type 1 with a simple quantitative deficiency of VWF. Patients with VWD type 3 generally do not have a useful response to DDAVP.267,270
The response to DDAVP in VWD type 2 variants is variable and frequently is unsatisfactory.179,270– 273 However, patients who will respond favorably are identifiable with a test infusion, which should be considered for all variants with low ristocetin cofactor activity.269 In VWD type 2N, DDAVP increases plasma VWF levels but often does not significantly increase factor VIII levels; this pattern is consistent with the inability of VWF type 2N to bind and stabilize factor VIII.272,273
In patients with VWD type 2B, DDAVP causes transient thrombocytopenia and spontaneous platelet aggregation,213 and the bleeding time usually is not shortened.195,213,274 Concerns over the potential for promoting thrombosis have led to the recommendation that DDAVP should not be used in type 2B VWD.213,271 Experience with DDAVP in this VWD subtype is very limited and the risk of thrombosis is not known, but no thrombotic complications have been described to date. In a few patients with VWD type 2B, DDAVP was therapeutically effective and did not cause a significant decrease in platelet count.275– 279 Thus, DDAVP may be acceptable therapy for a subset of patients with type 2B VWD.
Fibrinolytic inhibitors may be useful adjuncts for the control of nasopharyngeal and oral bleeding. Menorrhagia in women with VWD can be treated successfully with oral contraceptives.
Assessment of the risk of VWD is usually straightforward and requires only the determination of whether a family is affected by a dominant or recessive variant. For families affected with severe forms of VWD (type 3 and some type 2 variants), genetic counseling is the same as for any severe recessive disorder. Prenatal diagnosis has been accomplished for VWD type 3 by assays of factor VIII and VWF in fetal blood samples.280,281 The VWF multimer distribution in fetal blood may be diagnostic of type 2 VWD even if the levels of antigen are not depressed, provided there is no intercurrent disease that might consume large VWF multimers.282 The VWF gene is highly polymorphic; at least 32 marker systems are available for genetic studies in VWD.283 The most informative of these is a tetranucleotide repeat polymorphism in intron 40, with >98 alleles,284 and this system was used for prenatal diagnosis of severe VWD.285 DNA sequence polymorphisms also have been used to confirm the neonatal diagnosis of VWD.286,287
Carriers of the defective allele in mildly affected pedigrees could be identified with greater certainty by combining the currently employed VWF and factor VIII assays with analysis of DNA sequence polymorphisms. Such families should receive counseling, but most families do not choose to alter reproductive plans because of the mild phenotype.