Acquired von Willebrand syndrome and lymphoid neoplasms: A review of malignancy management, and propositions of practical recommendations

Abstract

Introduction Acquired von Willebrand syndrome (AWS) is a rare and potentially life‐threatening bleeding disorder. AWS is primarily associated with lymphocyte‐related disorders (AWS‐LRD), such as lymphoma and IgM monoclonal gammopathy of undetermined significance (MGUS), and plasmocyte‐related disorders (AWS‐PRD), such as non‐IgM MGUS and myeloma. Symptomatic treatments are important to control and prevent bleeding, but AWS‐LRD and AWS‐PRD can only be cured by targeting the responsible clonal cell. No reviews exist on this specific subgroup of AWS. Aim We performed a literature review to help manage these rare cases. Method Thirty‐two AWS‐PRD and 43 AWS‐LRD cases with data on malignancy treatment were reported in 56 articles from the Medline database. Results LRDs were exclusively indolent and primarily associated with IgM monoclonal compounds. LRDs and PRDs may be treated because of severe bleeding symptoms, but severe VWF deficiency did not necessarily correlate with severe bleeding. Immunosuppressive drugs in AWS‐PRD, including rituximab, provided an overall response rate of AWS (AWS‐ORR) of 30% (3/10), including short responses. Anti‐myeloma drugs provided an AWS‐ORR of 71.4% (20/28), with long‐lasting remissions. Bortezomib was the most commonly used drug and provided an AWS‐ORR of 66.7% (6/9), including therapeutic associations with other anti‐myeloma drugs. Autologous and allogeneic stem cell transplantation was performed in eight and two patients, respectively, and some details on the management of AWS during these procedures were provided. Rituximab in AWS‐LRD provided an AWS‐ORR of 60% (3/5), and a chemotherapy + rituximab regimen increased the AWS‐ORR to above 50%. Bleeding syndrome in AWS‐PRD and AWS‐LRD generally improved prior to AWS biological improvement. Conclusion Long term remission of AWS due to lymphoid neoplasms is attainable by treating the underlying clonal cell. Some data and recommendations are provided to help answer difficult questions, including treatment timing, choice of drug, and the timing of evaluations and treatment changes.

The Influence of Hypothyroid Metabolic Status on Blood Coagulation and the Acquired von Willebrand Syndrome

“…Other studies suggest that after the healing of a neoplastic disease, a VWS-ac is often no longer detectable. Nicol et al stated that long-term remission of VWS-ac can be reached by the treatment of the underpinning clonal cells of lymphoid tumors [ 38 , 39 ].…”

Sustained good response to rituximab in acquired von Willebrand syndrome

“…The lupus anticoagulant, an antiphospholipid (aPL) antibody, is defined as an immunoglobulin that inhibits phospholipid-dependent coagulation without suppressing individual coagulation factors. Lupus anticoagulant is found in various diseases, such as antiphospholipid antibody syndrome (APS) [1], habitual abortion [1], and idiopathic thrombocytopenic purpura (ITP) [2]. Lupus anticoagulant is clinically diagnosed based on a prolonged activated partial thromboplastin time (APTT) and thrombosis, rather than bleeding.…”

“…There is a theoretical risk of infection because of exposure to plasma, and side effects include an increased risk of thrombosis. There is a reported 60% response rate to rituximab when considering treatment of AvWS associated with lymphoid disorders [2]. Cases of AvWS associated with monoclonal B lymphocytosis [3] and MALT lymphoma [4][5][6] are reported with a good response to rituximab, with some patients receiving monotherapy, which resulted in normalization of the coagulation profile.…”

Autoimmune Diseases Affecting Hemostasis: A Narrative Review

“…Another somewhat common acquired bleeding disorder arises due to defects in, or reduction of, the adhesive plasma protein VWF, and this is conventionally termed AVWS [ 7 , 8 , 9 , 10 , 11 ]. In contrast to acquired hemophilia A, which can usually be shown to have a functionally inhibiting autoantibody basis, most forms of AVWS are not autoimmune related, and even if an autoantibody is identified, it is usually not functionally inhibiting.…”

“…For example, auto-immune mediated antibodies generated against clotting factors can lead to bleeding, of which acquired hemophilia A (antibodies against FVIII) is the most common [ 1 , 2 , 3 , 4 , 5 , 6 ]. Acquired von Willebrand syndrome (AVWS) represents an additional example of an acquired bleeding disorder [ 7 , 8 , 9 , 10 , 11 ], sometimes associated with antibodies against von Willebrand factor (VWF), an adhesive plasma protein that otherwise facilitates attachment and immobilization of blood platelets to the sites of vascular injury, thereby promoting platelet plug formation. Alternatively, auto-immune mediated generation of antibodies against various hemostasis components can promote a prothrombotic milieu.…”