Acquired von Willebrand Syndrome in Waldenström's macroglobulinemia revealed by an angiodysplasia: a case report

¹University of Tunis El Manar, Faculty of Medicine of Tunis, 1007, Hospital of Aziza Othmana, Service of Clinical Haematology, Tunis, Tunisia

^&Corresponding author
Wiem Chaaouri, University of Tunis El Manar, Faculty of Medicine of Tunis,1007, Hospital of Aziza Othmana, Service of Clinical Haematology, Tunis, Tunisia

Introduction    

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that resembles inherited von Willebrand disease (vWD) in laboratory findings and clinical presentation [1]. Its prevalence is estimated at 0.04% in the general population [2]. AVWS was first described in 1968 in a 7-year-old child with systemic lupus erythematosus [2], and approximately 300 cases have been reported since [2]. AVWS most often occurs secondary to other conditions, with lymphoproliferative neoplasms (48%), myeloproliferative neoplasms (15%), cardiovascular diseases (21%), solid tumours (5%), and autoimmune disorders (2%) being the most frequent associations [3]. Monoclonal gammopathy of undetermined significance and multiple myeloma are the most common lymphoproliferative disorders complicated by AVWS [3]. Characteristic features include late onset, absence of previous bleeding, and negative family history. We report a case of a 61-year-old woman with AVWS in Waldenström's Macroglobulinemia revealed by gastrointestinal angiodysplasias, highlighting the importance of recognising AVWS in lymphoproliferative disorders.

Patient and observation     

Patient information: a 61-year-old woman was referred to our haematology centre for evaluation of lymphocytosis (11 G/L) associated with bicytopenia. She had no previous history of bleeding, no personal or family history of vWD or hemorrhagic tendency, and no relevant past medical treatment. Her psychosocial history was unremarkable.

Clinical findings: physical examination revealed splenomegaly extending 7.8cm below the left costal margin. During the diagnostic workup, the patient developed gastrointestinal bleeding manifested by melena and rectal bleeding.

Timeline of current episode: the patient was initially evaluated for cytopenias and lymphocytosis in September 2023. During staging investigations in October 2023, she developed gastrointestinal bleeding, a vascular lesion in the gastroduodenal region, and panel B shows a similar lesion in the colon. It is characterized by dilated, tortuous vessels with active bleeding requiring treatment with argon plasma coagulation, which led to endoscopic exploration and hemostatic management. Hemostatic abnormalities were subsequently identified (Figure 1). Treatment targeting the underlying lymphoproliferative disorder was initiated in November 2023, and in January 2024, the patients' hemostatic parameters normalised with no further clinically significant bleeding occurring.

Diagnostic assessment: peripheral blood smear showed mature lymphocytosis with lymphocytes exhibiting polar cytoplasmic projections. Immunophenotyping was consistent with a chronic lymphoproliferative disorder (CD19+, CD5−, strongly CD20+, weakly CD23+). Serum protein electrophoresis revealed a monoclonal gammopathy confirmed as IgM-kappa. Bone marrow biopsy demonstrated lymphoplasmacytic lymphoma with 10% infiltration. Staging showed infradiaphragmatic lymphadenopathy and multinodular splenomegaly. Upper gastrointestinal endoscopy revealed gastroduodenal and colonic angiodysplasias treated with argon plasma coagulation (Figure 1). Hemostasis investigations and specific von Willebrand factor (vWF) assays are summarised in Table 1.

Diagnosis: Waldenström's Macroglobulinemia complicated by AVWS presenting with gastrointestinal angiodysplasias.

Therapeutic interventions: the patient received rituximab, cyclophosphamide, and dexamethasone as first-line therapy. After disease progression following three cycles, salvage therapy with rituximab and bendamustine was initiated.

Follow-up and outcome of interventions: after two cycles of first-line therapy, hemostatic parameters normalised, and no further clinically significant bleeding occurred. Despite hematologic progression after three cycles, salvage therapy achieved a partial response.

Patient perspective: the patient reported satisfaction with the comprehensive care received, particularly regarding the rapid control of bleeding and close monitoring during treatment.

Informed consent: written informed consent was obtained from the patient for publication of this case report and accompanying images in accordance with the CARE guidelines and the Declaration of Helsinki.

Discussion     

AVWS, although described more than 50 years ago, has gained renewed attention because of its association with cardiovascular diseases, solid tumours, hematologic malignancies, and autoimmune disorders [4]. Unlike inherited VWD, AVWS generally results from increased clearance, proteolysis, or functional impairment of vWF, rather than reduced production [4,5]. In lymphoproliferative disorders, several mechanisms have been proposed, including VWF-specific inhibitors, adsorption of VWF onto malignant cells, immune complex formation, and enhanced proteolytic degradation of VWF multimers [5-8]. In Waldenström's macroglobulinemia, elevated IgM levels and hyperviscosity may increase shear stress, promoting ADAMTS13-mediated cleavage of high-molecular-weight multimers (HMWM), which are critical for normal hemostasis [5].

The diagnosis of AVWS is based on laboratory findings similar to inherited VWD in the absence of personal or family history of bleeding [1]. Multimer analysis is particularly helpful, as AVWS typically shows partial or complete loss of HMW multimers; however, this assay was not available in our setting. The absence of anti-VWF antibody testing also represents a limitation. Beyond hemostasis, VWF plays a role in angiogenesis regulation [9]. Loss of HMW multimers has been associated with gastrointestinal angiodysplasias and recurrent bleeding, especially in conditions characterised by high shear stress, such as aortic stenosis and left ventricular assist devices [9,10]. We hypothesise that hyperviscosity related to IgM monoclonal gammopathy in our patient contributed to HMW multimer depletion and subsequent angiodysplasia formation.

Management of AVWS primarily targets the underlying disorder, along with control and prevention of bleeding [5]. As illustrated in this case, treatment of the hematologic malignancy led to stabilisation of the hemostatic abnormalities. This report underscores the importance of considering AVWS in patients with lymphoproliferative disorders presenting with unexplained bleeding and gastrointestinal angiodysplasias.

Conclusion     

This case underscores the need to consider AVWS in patients with lymphoproliferative disorders presenting with unexplained bleeding, particularly in the presence of gastrointestinal angiodysplasias. Optimal management requires treatment of the underlying disease, supported by appropriate hemostatic therapy and close multidisciplinary collaboration.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All authors contributed to the study's conception and design. Wiem Chaaouri and Malek Sayadi were involved in patient management and data collection. Wiem Chaaouri and Wafa Miled performed the literature review and contributed to data interpretation. Wiem Chaaouri drafted the manuscript. Raoudha Mansouri, Raihane Benlakhel and Karima Kacem critically revised the manuscript for important intellectual content and supervised the work. All authors read and approved the final version of the manuscript.

Acknowledgments     

The authors would like to thank the medical and laboratory staff involved in the care of this patient for their valuable contribution.

Table and figure     

Table 1: evolution of hemostasis test results before treatment and after two cycles of chemotherapy

Figure 1: gastrointestinal angiodysplasia identified on endoscopic examination

References