Acquired Von Willebrand Disease Associated with Hematologic Malignancies: Case Series and Literature Review

Objective: To describe a single institution experience of AvWD of the spectrum of presentation in hematologic malignancies.

Introduction: Acquired von Willebrand disease (AvWD) is a rare acquired bleeding disorder characterized by mucocutaneous bleeding and functional alterations in von Willebrand factor (vWF). AvWD can be caused by numerous conditions but we are going to focus on those associated with hematologic malignancies. The pathogenic mechanisms responsible for the vWF abnormalities can include abnormal clearance due to binding of paraproteins, inhibition of vWF, adsorption to the surface of platelets, proteolysis from increased fluid shear stress, and decreased synthesis.

Methods: Clinical review of 4 cases of AvWD at a tertiary academic medical center from January 2016 to January 2022.

Results: Case 1: 57-year-old female with history of chronic thrombocytosis of 1.6 million and was diagnosed with a JAK2 V617F mutation positive essential thrombocythemia and concurrent iron deficiency anemia. She was placed on low dose aspirin for thromboprophylaxis and presented with hematochezia with a drop in hemoglobin from 9.7g/dL to 4.3g/dL, platelets were 857k/uL. At that time her aPTT was mildly elevated at 37.0 (normal 36.5) This prompted testing for von Willebrand disease which showed low vWF activity 50% and vWF GP I binding activity 47% with normal vWF antigen activity 82% and factor VIII clotting activity of 100 IU/ml. Aspirin was held and hydroxyurea initiated at 1000mg daily with clinical response. Coagulation testing including aPTT and vWF antigen, Activity and multimers normalized after cytoreduction of her platelets with hydrea. Case 2: 75-year-old male with history of stroke on aspirin. We saw the patient for erythrocytosis and made the diagnosis of JAK 2 V617F mutation positive polycythemia rubra vera. Phlebotomy was initiated however, he presented with large ecchymoses at the venipuncture sites following phlebotomy. Testing showed quantitative vWF and factor VIII were normal, abnormal GPIbM: vWF ratio and loss of highest molecular weight multimers. He was maintained on hydroxyurea 1500mg daily for target hematocrit of 40 g/dL and low dose aspirin thromboprophylaxis without recurrent bleeding. Case 3: A 68-year-old female who we were following with a history of an IgM monoclonal gammopathy of undetermined significance (MGUS) reported mild ecchymosis on the extremities. Testing showed low factor VIII level of 34% and low vWF antigen and activity at 29% and 22%, and normal vWF multimers. She has been observed without any therapy given lack of clinically significant bleeding. Three years later, she has now developed of cytopenias and bone marrow biopsy showed 30 - 40% lymphoplasmacytic infiltrate consistent with progression to Waldenström Macroglobulinemia. Case 4 60 year-old-male with history of an IgG lambda MGUS who presented with new onset recurrent melena without a source of bleeding found on endoscopy. Testing showed decreased vWF antigen 30% and vWF activity 21%, normal factor VIII activity 69% and all multimers decreased consistent with AvWD from his known MGUS. His recurrent mucosal bleeding was managed with weekly Humate P. Revlimid 10mg per day was initiated for MGUS. Two months later, his indices improved with normalized VWF multimers and VWF antigen 70% and factor VIII activity 142%, and with now only mildly decreased VWF activity at 48%. Recurrent bleeding ceased.

Conclusions: Patients with hematologic malignancies may present with mucocutaneous bleeding which may mimic congenital vWD however, AvWD should be considered in this population of patients. In addition, patients with AvWD can present with varying degrees of bleeding which might be mistaken for platelet dysfunction due to the underlying malignancies or the addition of aspirin or anticoagulation. One must maintain high clinical suspicion for AvWD with new onset bleeding in setting of known myeloproliferative or lymphoproliferative disorder. vWF antigen, activity, factor VIII activity and multimer testing should be obtained to secure the diagnosis. Treatment of the underlying disorder will result in clinical and laboratory improvement.

Liles:Vifor: Other: presently and the Sub I or PI on trials; Biogene: Other: presently and the Sub I or PI on trials; Novartis: Other: presently and the Sub I or PI on trials; Takeda: Other: presently and the Sub I or PI on trials; Shire,: Other: presently and the Sub I or PI on trials; Incye,: Other: presently and the Sub I or PI on trials; Apellis: Other: presently and the Sub I or PI on trials; Sun Pharma: Other: presently and the Sub I or PI on trials; Momenta pharmaceuticals: Other: presently and the Sub I or PI on trials; PiCori: Other: I also am the Site Sub I for 2 PiCori grants in sickle cell anemia..