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AvWS focused for hematologists
Treatment
There are three main treatment goals for patients with AvWS: the control of acute bleeding, its prevention in high-risk situations, and the achievement of a stable remission or cure of the syndrome.46,47 Removal of the underlying disorder (i.e. by means of surgery, chemother- apy, radiotherapy and/or immunosuppressants), which is not within the scope of this review, is the only potentially curative approach. However, treatment of the associated condition may not be feasible, and a partial remission does not always ameliorate the bleeding symptoms.
As far as the hemostatic therapies are concerned, a range of different medications have been used: desmopressin (DDAVP), vWF/FVIII concentrates, antifibrinolytic agents, high-dose intravenous immunoglobulins (HDIVIg), plasmapheresis and recombinant activated factor VII (rFVIIa).46,47
The synthetic analog of DDAVP, given intravenously or subcutaneously at the dose of 0.3 mg/kg, was used to con- trol or prevent bleeding in the AvWS.48,49 The ISTH registry reported an overall success rate with DDAVP of approxi- mately 30%, although this varied according to the under- lying disorder: lower in cardiovascular disorders (10%) and myeloproliferative neoplasms (21%), and higher in autoimmune (33%) and lymphoproliferative (44%) disor- ders.16-18 In a prospective trial performed in ten patients with MGUS, plasma vWF levels increased in all patients after DDAVP, but the increase was short-lasting.44 A short plasma half-life of vWF following DDAVP administration has also been observed in the context of other lymphopro- liferative disorders and is thought to be related to the pres- ence of anti-vWF antibodies. A transient effect of DDAVP was also observed in patients with myeloproliferative neoplasms, mainly due to adsorption or proteolytic cleav- age of the released vWF. It is advisable to closely monitor FVIII:C and vWF:RCo/vWF:CB plasma levels after DDAVP in order to maintain these at levels that are suffi- cient to prevent or treat bleeds.
As far as replacement therapy is concerned, several plas- ma-derived concentrates containing vWF have been used in AvWS.16-18 In the ISTH registry, vWF/FVIII concentrates showed a favorable response in approximately 40% of cases,18 with dosages ranging between 30-100 vWF:RCo units/kg. The half-life of infused vWF is shorter than in inherited vWD, thus requiring higher doses of vWF/FVIII concentrate to ensure adequate hemostatic plasma lev- els.16-18 Plasma FVIII:C and vWF:RCo must be monitored when administering DDAVP, particularly in patients undergoing invasive or surgical procedures.
The antifibrinolytic agents most commonly used in
AvWS are the lysine analogs ε-aminocaproic acid, admin- istered at a dose of 50-60 mg/kg every 4-6 hours, and tranexamic acid, at a dose of 20-25 mg/kg every 8-12 hours.50 These drugs can be given orally, intravenously or topically, and act by inhibiting plasminogen activation. Antifibrinolytics are primarily used as adjuvants together with DDAVP or vWF/FVIII concentrates for surgery and bleeding, particularly at sites with high fibrinolytic activi- ty (i.e. gastrointestinal and oral tracts); however, these drugs may be used alone for minor bleeding episodes.
The ISTH registry reported a 33% success rate in clinical cases receiving HDIVIg in AvWS, especially for lympho- proliferative disorders (37%), solid tumors (100%), and immunological diseases (50%).16-18 HDIVIg is especially useful in cases associated with MGUS.44 In a prospective trial which enrolled ten patients with AvWS and MGUS, HDIVIg was more effective than DDAVP and VWF/FVIII concentrates because there was a more sustained increase in FVIII/VWF activities and shortening of bleeding time for at least 15-20 days in all IgG-MGUS cases.44 In contrast, no response was observed in patients with IgM class MGUS (IgM-MGUS).44 In addition, prophylactic infusions of HDIVIg every 21 days stopped recurrent gastrointestinal bleeding in patients with IgG-MGUS. The mechanisms of action of HDIVIg may involve an anti-idiotype effect, blockage of reticulo-endothelial Fc-receptors, or capture of the circulating immune complexes by the immunoglobu- lins.53 The recommended doses of HDIVIg are 1 g/kg for two days or 0.4 g/kg for five days.51-54 The increase in vWF and FVIII:C levels usually occurs within 24-48 hours and may last up to 3-4 weeks; thus, additional courses of HDIVIg every 21 days are necessary to maintain a clinical response. On the whole, HDIVIg represent an important therapeutic tool for the management of AvWS, especially for cases associated with IgG monoclonal gammopathies, lymphoproliferative disorders, and multiple myeloma associated IgG paraproteins.44 Due to the delay in the post- infusion increase in vWF and FVIII:C levels, HDIVIg is not effective in the management of acute bleeding; in these cases, the medication must be administered together with shorter-acting agents such as DDAVP and vWF/FVIII con- centrates.51-54 The main goal of plasmapheresis is to tem- porarily eliminate autoantibodies and paraproteins from the circulation. This procedure is particularly effective in IgM-MGUS, which generally responds poorly to other treatments. Finally, rFVIIa, usually administered at a dose of 90 mg/kg for a median of three doses, has been success- fully used when bleeding associated with AvWS is unre- sponsive to DDAVP and vWF/FVIII concentrates.55-59
Table 2 summarizes the multiple therapeutic strategies available for the treatment or prevention of bleeding in
Table 2. Hemostatic therapies in acquired von Willebrand syndrome associated with different underlying diseases.
Underlying diseases
Cardiovascular
Lymphoproliferative
- IgG MGUS
- IgM MGUS
- Lymphoma, myeloma
Myeloproliferative Autoimmune
Therapy
vWF/FVIII concentrates, antifibrinolytics
HDIVIg
Plasmapheresis, DDAVP, vWF/FVIII concentrates, antifibrinolytics, rFVIIa DDAVP, vWF/FVIII concentrates, antifibrinolytics, rFVIIa, HDIVIg
DDAVP, vWF/FVIII concentrates, antifibrinolytics HDIVIg, DDAVP, vWF/FVIII concentrates
MGUS: monoclonal gammopathy of unknown significance; vWF: von Willebrand factor; FVIII: factor VIII; HDIVIg: high-dose intravenous immunoglobulin; DDAVP: desmopressin; rFVIIa: recombinant activated factor VII.
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