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HOW I TREAT
From the Angelo Bianchi Bonomi Hemophilia and
Thrombosis Center and the Department of Internal Medicine, IRCCS
Maggiore Hospital, University of Milan, Italy.
Von Willebrand disease (vWD) is a frequent inherited disorder of
hemostasis that affects both sexes. Two abnormalities are characteristic of the disease, which is caused by a deficiency or a
defect in the multimeric glycoprotein called von Willebrand factor: low
platelet adhesion to injured blood vessels and defective intrinsic
coagulation owing to low plasma levels of factor VIII. There are 2 main
options available for the treatment of spontaneous bleeding episodes
and for bleeding prophylaxis: desmopressin and transfusional therapy
with plasma products. Desmopressin is the treatment of choice for most
patients with type 1 vWD, who account for approximately 70% to 80% of
cases. This nontransfusional hemostatic agent raises endogenous factor
VIII and von Willebrand factor 3 to 5 times and thereby corrects both
the intrinsic coagulation and the primary hemostasis defects. In
patients with the more severe type 3 and in most patients with type 2 disease, desmopressin is ineffective or is contraindicated and it is
usually necessary to resort to plasma concentrates containing both
factor VIII and von Willebrand factor. Concentrates treated with
virucidal methods should be preferred to cryoprecipitate because they
are equally effective and are perceived as safer.
(Blood. 2001;97:1915-1919) Von Willebrand disease (vWD) is a common inherited
bleeding disorder caused by the deficiency or dysfunction of von
Willebrand factor (vWF) resulting from mutations in the gene encoding
this multimeric glycoprotein. A comprehensive review on vWD and vWF has
been recently published.1 vWF performs 2 major functions in primary hemostasis and in intrinsic blood coagulation vWD is phenotypically heterogeneous and is classified into 3 different
types2 (Table 1). Type 1 refers to partial, quantitative deficiency vWF, and the more severe
type 3 refers to complete deficiency. Type 2 vWD refers to qualitative
abnormalities of vWF, usually measurable in normal amounts in plasma,
and is further subdivided into 4 subtypes Although the treatment of patients with hemophilias A and B is
facilitated by the close relation between the content of VIII and
factor IX in replacement material, plasma levels attained after
infusion, and clinical efficacy, this model cannot be easily translated
to the evaluation of products for the treatment of vWD because it is
still unclear which VIII or vWF measurement in therapeutic products or
in patient plasma better correlates with the severity of clinical
bleeding and the efficacy of treatment. The situation is further
complicated by the fact that vWD subtypes respond differently to
treatment. Two main therapeutic agents are used to stop spontaneous
bleeding and to prevent bleeding at the time of surgical procedures:
the nontransfusional agent desmopressin and blood products that contain
VIII and vWF concentrated from plasma. Additional forms of treatment
are platelet concentrates, synthetic fibrinolysis inhibitors, and oral
estrogen-progestogen preparations that in some clinical situations are
adjunctive or alternative to the 2 main treatments.
Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic
analogue of the antidiuretic hormone vasopressin that was originally
designed for the treatment of diabetes insipidus. When administered to
healthy volunteers or patients with mild hemophilia and
vWD,4 desmopressin increases VIII and vWF transiently by releasing these moieties from storage sites into plasma. The mode of
action of the compound is only partially understood. Endothelial cell
Weibel-Palade bodies appear to be the source of vWF, but the source of
VIII has not been determined. Desmopressin induces vWF release into
plasma by binding to the vasopressin V2 receptor and thereby activating
cyclic adenosine monophosphate-mediated signaling in vascular
endothelial cells.5
The first clinical trial of desmopressin was successfully performed in
1977; its aim was to avoid the use of blood products in patients with
mild hemophilia and vWD who need dental extractions and other surgical
procedures.6 The obvious advantage of this compound is
that it is relatively inexpensive and carries no risk for transmitting
blood-borne infectious agents. When infused intravenously over 30 minutes at a dose of 0.3 µg/kg diluted in 50 to 100 mL saline,
desmopressin is expected to increase plasma VIII and vWF 3 to 5 times
above the basal levels within 30 minutes.6-8 In general,
high VIII-vWF concentrations last in plasma for at least 8 to 10 hours.8 Because the response in each patient is consistent on different occasions, a test dose of desmopressin administered at the
time of diagnosis helps to establish the individual patterns of
response.4 Patients with baseline plasma levels of
VIII-vWF measurements in the range of 10 to 20 IU/dL or more are those who are more likely to reach postdesmopressin levels sufficient to
attain hemostasis, taking into account variables such as type and
severity of the bleeding episode and levels of VIII-vWF that must be
maintained to secure hemostasis. Infusions can be repeated every 12 to
24 hours, if necessary. Even though most patients with mild hemophilia
A, treated repeatedly with desmopressin, become less responsive to
therapy, this problem is less frequent and less prominent in
patients with type 1 vWD.7 The drug is also available in
concentrated forms for subcutaneous and intranasal administration (at
doses of 0.3 µg/kg and 300 µg, respectively), which can be
convenient for home treatment.4,8
Side effects of desmopressin are usually mild tachycardia, headache,
and flushing. These symptoms are attributed to the vasodilating effects
of the drug and can often be attenuated by slowing the rate of
infusion. Hyponatremia and volume overload due to the antidiuretic
effect of desmopressin are relative rare if fluid intake is not
excessive during treatment. A few cases have been described, mostly in
young children who received closely repeated infusions.9
Even though no episodes of thrombosis have been reported in vWD
patients treated with desmopressin, this compound should be used with
caution in elderly patients with cardiovascular disease because
myocardial infarction and stroke have occurred in a few treated
patients with hemophilia and uremia.10,11 These thrombotic
events are likely to be related to the transient appearance in plasma
of ultralarge vWF multimers that originate from the endothelial cells
and aggregate platelets directly in conditions of high shear stress,
such as those occurring in stenotic arteries.4
Desmopressin has little or no oxytocic activity and has been used by me
without mishap during the early period of pregnancy in 31 women
(including carriers of hemophilia A and patients with vWD) with low
VIII levels to prevent bleeding at the time of invasive diagnostic
procedures, such as chronic villus sampling and amniocentesis
(unpublished observations).
Desmopressin is most effective in patients with type 1 vWD,
particularly in those who have releasable vWF in storage sites, a
condition usually reflected by normal vWF levels in
platelets.12 In these patients VIII, vWF, and bleeding
time (BT) are usually corrected to normal values by
desmopressin.12 In other vWD subtypes, responsiveness is
varied (Table 2). A poor and
short-lasting response is seen in patients with the variant of type 1 vWD that is characterized by low levels of platelet vWF,12
perhaps because low levels in platelets are paralleled by low levels of
releasable vWF in storage sites. In type 2A vWD, VIII:c levels are
usually increased by desmopressin, but the BT is shortened in only a
few patients. Desmopressin is contraindicated in type 2B vWD because of
the transient appearance of thrombocytopenia.13 There is little experience in type 2M vWD, but a poor response is predicted because vWF is dysfunctional in this subtype. In type 2N vWD, VIII:c
levels increase after desmopressin,14 but released VIII circulates for a relatively short time in patients' plasma because the
stabilizing effect of vWF on VIII is impaired by gene mutations affecting the VIII binding site of vWF.1 Therefore, plasma concentrates containing the VIII and vWF forms are preferable. Patients
with type 3 vWD are usually unresponsive to desmopressin because they
lack releasable stores of vWF.
Two other types of nontransfusional therapy are sometimes used in
the management of vWD
Transfusional therapy with plasma products containing both VIII and vWF is the treatment of choice when bleeding occurs or must be prevented and the predicted response to desmopressin is considered suboptimal for hemostasis. VIII and vWF may be infused as fresh frozen plasma (FFP), but the large volumes required severely limit its use. Cryoprecipitate contains 5 to 10 times more VIII and vWF than FFP (each bag contains approximately 80-100 IU). Early studies indicate that cryoprecipitate administered every 12 to 24 hours normalized plasma VIII levels and stopped or prevented bleeding in vWD.16 Based on these observations, cryoprecipitate has been the mainstay of treatment for many years. However, virucidal methods cannot be applied to cryoprecipitate as currently produced by blood banks, and this product carries a small but definite risk for transmitting blood-borne infectious agents. Therefore, virus-inactivated VIII-vWF concentrates, originally developed for the treatment of hemophilia A, are perceived as safer and are preferred in the management of patients with vWD unresponsive to desmopressin.17 Two commercially available concentrates have been evaluated more extensively than others, and clinical studies have demonstrated their efficacy in preventing or stopping bleeding.18,19 One, licensed in the United States and in several European countries for the treatment of vWD, contains relatively larger amounts of VIII:c than of vWF measured as vWF:RCoF (approximately 2-3 times more in terms of IU). The virucidal method adopted is pasteurization.18 The other, licensed only in Europe so far, differs because it contains similar relative amounts of VIII:c and vWF:RCoF.19 Two virucidal methods, solvent-detergent and heating at high temperature, are included in the manufacturing step with the goal to inactivate both enveloped and nonenveloped virus.19 Other virally inactivated VIII-vWF concentrates have been successfully used in vWD patients, but clinical experience is more limited.20-24 Very high-purity VIII concentrates, obtained by immuno-affinity chromatography on monoclonal antibodies, contain very small amounts of vWF, and the available preparations of recombinant VIII contain none. They are unsuitable for vWD management because the plasma half-life of infused VIII:c is short (1 hour or less)25 owing to the absence of its carrier vWF both in the actual concentrates and in vWD patients' plasma. Recently, a chromatography-purified concentrate particularly rich in vWF but with a low VIII content has also been evaluated.26,27 This concentrate was clinically efficacious when tested in a small number of patients with type 3 vWD.27 Efficacy and safety are now under evaluation in Europe in larger series of patients. The dosages that I recommend for the control or prevention of bleeding
are summarized in Table 3. Dosages are
expressed in IU/kg VIII:c because most of the available concentrates
manufactured for the treatment of patients with hemophilia A are
labeled in terms of VIII:c content only. Because VIII:c in vWD patients
has a longer half-life than it does in patients with hemophilia A (24-26 vs 12-14 hours),18,19 the infusion of one daily
dose is sufficient to reach and maintain adequate plasma levels for the
treatment of spontaneous bleeding episodes and to prevent excessive
bleeding until healing is complete, depending on the site and extent of
surgery. Because in the United States the Food and Drug Administration
is requiring that plasma products licensed for treatment of vWD
patients be labeled in terms of the actual defective protein to be
replaced,28 the solvent-detergent, heat-treated concentrate is labeled in terms of vWF:RCoF
content.19 The doses of this concentrate that I recommend
for their demonstrated efficacy in a large, prospective clinical trial
are 40 to 60 IU/kg (50-75 IU/kg in children because of the lower in
vivo recovery), which usually results in vWF:RCoF plasma levels of 80 to 120 U/dL or higher.19 Even though the plasma half-life
of vWF:RCoF is much shorter than that of VIII:c (6-8 vs 24-26 hours),18,19,26 usually these doses do not have to be
repeated more often than every 24 hours, but sometimes treatment
intervals must be tailored to the clinical situation.
It is usually not necessary to carry out laboratory tests to monitor replacement therapy in patients with spontaneous bleeding episodes. For surgical procedures, I recommend measuring VIII:c every 12 hours on the day of surgery and then every 24 hours. The VIII:c response can be predicted on the basis of pharmacokinetic data, indicating that 1 IU/kg will increase plasma VIII:c levels by approximately 2 U/dL (1.5 U/dL in children).18,19 Those who use concentrates labeled in terms of vWF:RCoF content may choose to monitor the plasma levels of this moiety, though it is more complex to measure in the clinical setting and is less standardized than VIII:c levels. It remains to be demonstrated whether newer laboratory measurements, such as the collagen binding assay, will be simpler and more predictive of outcome.29,30 Monitoring the skin bleeding time is usually not necessary. The prolonged bleeding time is frequently not normalized or even shortened in patients treated with VIII-vWF concentrates.17,31 There are probably multiple reasons for the inconsistent effects of plasma products on the BT. So far, no concentrate contains a fully functional vWF, as tested in vitro by evaluating the multimeric pattern and using functional assays, because marked vWF proteolysis occurs during purification resulting from the action of platelet and leukocyte proteases contaminating plasma used for fractionation.32 Despite no or partial correction of the BT, major surgical procedures are successfully carried out and spontaneous bleeding episodes are controlled after the infusion of VIII-vWF concentrates.18,19 In the relatively rare instances in which the BT remains prolonged and bleeding is not controlled, platelet concentrates (given immediately after VIII-vWF-containing preparations, at doses of 4-5 × 1011 platelets) are effective, particularly in patients with type 3 vWD, both in terms of BT correction and control of hemorrhages.33,34 Platelets from patients with type 3 vWD lack vWF completely, and there is no uptake of the protein from plasma after the infusion of concentrates.33,34 The hemostatic effectiveness of the transfusion of normal platelets likely results because these cells transport and localize vWF at sites of vascular injury. From a practical standpoint, it must be emphasized that in the largest prospective study carried out thus far in vWD patients, platelet concentrates were necessary to prevent or stop bleeding in one patient only.19
There is no evidence that vWD, even the severe type 3, impairs
fertility in affected women or that miscarriages are more frequent in
these patients than in women without vWD.35 During normal pregnancy, vWF and VIII levels tend to rise spontaneously in women with
types 1 and 2 vWD,36 but this rise does not start until the 10th to 11th week of gestation. Because the degree of rise during
pregnancy is variable, patients with type 1 vWD should be monitored
with VIII:c assays in the days before parturition and for 1 to 2 weeks
afterward
Anti-vWF alloantibodies develop after multiple transfusions in 10% to 15% of patients with type 3 vWD.38 The prevalence and natural history of this complication is roughly similar to that occurring in patients with hemophilia A,39,40 in whom the infusion of vWF concentrates not only is ineffective, it may cause postinfusion anaphylactic reactions because of the formation of immune complexes that activate the complement system.41,42 These reactions may be life-threatening.42 There is little experience in the management of these patients with agents other than VIII-vWF concentrates. I was able to successfully treat a patient who had previously had life-endangering anaphylactic reactions and was now undergoing emergency abdominal surgery with recombinant VIII because this product, completely devoid of VWF, was the only one that did not cause the formation of immune complexes and anaphylactic reactions.43 Because of the very short half-life of VIII devoid of its vWF carrier, recombinant VIII had to be administered by continuous intravenous infusion, at very large doses sufficient to maintain VIII:c levels greater than 50 U/dL for 10 days after surgery.43 Even though there is limited clinical experience on the use of recombinant activated factor VII in these patients, there are theoretical reasons to believe that this VWF-free product might provide nonspecific surgical hemostasis bypassing the defect in intrinsic coagulation.
The different options available for the management of von
Willebrand disease are summarized in Table
4. Treatment of spontaneous bleeding
episodes and their prevention at the time of invasive procedure is
relatively simple and can certainly be tackled by the average clinical
hematologist with access to a minimum of laboratory testing (factor
VIII:c assays). However, the patients must be well characterized
phenotypically because the choice of treatment must be tailored to the
different types and subtypes of the disease. Such characterization is
not simple. In most clinical centers, it is probably not worthy to set
up relatively complicated tests such as multimer analysis and vWF:RCoF
assay when samples can be sent for analysis to more expert laboratories
that have become proficient during the study of large series
of patients.
Submitted November 9, 2000; accepted December 6, 2000.
Reprints: Pier Mannuccio Mannucci, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Via Pace 9, 20122 Milan, Italy; e-mail: piermannuccio.mannucci{at}unimi.it.
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Abstract
Introduction
it mediates the adhesion of platelets at sites of vascular injury, and it stabilizes coagulation factor VIII (VIII) in plasma. In vWD the impairment of these functions is expressed phenotypically by low plasma
levels of VIII coagulant activity (VIII:c) and by a prolonged skin
bleeding time, at least in the most severe and clinically relevant
cases. Bleeding symptoms are usually mild and are characterized by
prolonged oozing after minor and major surgery and by mucosal tract
hemorrhages such as epistaxis and menorrhagia. Only some of the more
severely affected patients have soft-tissue bleeding, such as muscle
hematomas and hemarthroses. Childbirth is often a cause of concern,
particularly in the postpartum period.
