Combination Venetoclax and Rituximab: A Novel Approach to Gastrointestinal Hemorrhage from Acquired Von Willebrand Syndrome in the Setting of Relapsed Chronic Lymphocytic Leukemia

Case Report

Ann Hematol Oncol. 2021; 8(12): 1379.

Combination Venetoclax and Rituximab: A Novel Approach to Gastrointestinal Hemorrhage from Acquired Von Willebrand Syndrome in the Setting of Relapsed Chronic Lymphocytic Leukemia

Heald JT¹* and Oleszewski RT²

¹Department of Internal Medicine, Eisenhower Army Medical Center, USA

²Department of Hematology and Oncology, Eisenhower Army Medical Center, USA

*Corresponding author: Heald JT, Department of Internal Medicine, Eisenhower Army Medical Center, 300 Hospital Rd, Fort Gordon, Ga 30905, USA

Received: September 20, 2021; Accepted: October 14, 2021; Published: October 21, 2021


Congenital Von Willebrand Disease (VWD) is the most common bleeding diathesis in humans with a prevalence of one percent in the general population. However, acquired Von Willebrand Syndrome (aVWS) is a rare coagulopathy that has been reported to be associated with numerous conditions and occurs through a variety of mechanisms. In addition to causing bleeding diathesis due to coagulopathy, there is evidence that demonstrates Von Willebrand’s Factor (VWF) deficiency leads to aberrant blood vessel formation. Treatment for this disease is directed at stabilization of associated hemorrhage and correction of underlying etiology. We present the case of a patient with aVWS disease due to relapse of Chronic Lymphocytic Leukemia (CLL) complicated by gastrointestinal hemorrhage from gastric and small bowel angiodysplasia treated with rituximab and venetoclax, previously unreported in the medical literature.

Keywords: Acquired Von Willebrand Syndrome; Chronic Lymphocytic Leukemia; Angiodysplasia; Rituximab; Venetoclax


VWD: Von Willebrand Disease; aVWS: acquired Von Willebrand Syndrome; VWF: Von Willberand Factor; CLL: Chronic Lymphocytic Leukemia; ISTH: International Society on Thrombosis and Haemostasis; DDAVP: Desmopressin; IVIG: Intravenous Immune Globulin


Congenital Von Willebrand disease is the most common bleeding diathesis in humans with a prevalence of approximately 1 percent with 1 in 10,000 to 1 in 100,000 displaying symptoms [1,2]. However, aVWS is a rare coagulopathy with an unknown true prevalence. Approximately 700 reported cases exist in the medical literature since first being described in 1968 [3]. Originally described in a patient with Systemic Lupus Erythematosus, aVWS has subsequently been reported in the setting of various malignancies, autoimmune disorders, severe aortic stenosis and left ventricular assist devices (LVAD) [4]. There is also evidence that deficiencies in Von Willebrand factor can lead to neovascularization notably angiodysplasia [5-8]. This phenomena has been most widely described in patients with LVADs or severe aortic stenosis 7 but seemingly rare in patients with lymphoproliferative derived aVWS. Current treatment guidelines per the International Society on Thrombosis and Haemostasis (ISTH) include Desmopressin (DDAVP), Factor eight/VWF concentrates, Intravenous Immune Globulin (IVIG), or plasmapheresis. When possible, correction of underlying disease process is particularly important [9]. In this report, we present a patient with aVWS due to relapsed CLL, complicated by gastrointestinal hemorrhage from angiodysplasia, treated with rituximab and venetoclax.

Case Presentation

Patient was a 64 year old male with history of CLL (genotype zap70 (+), CD38 (+), IgGVH, deletion 11, p53 (+)) in clinical remission following rituximab and fludarabine therapy (2007 to 2011) who presented to the emergency department with symptomatic anemia and melena. He had been followed in the Oncology clinic for rising leukocytosis since 2017 with cell counts consistently eighty to one hundred thousand. He had deferred repeat therapy due to an absence of symptoms. As demonstrated in Table 1, initial laboratory evaluation on admission was notable for hemoglobin of 6.7g/dL, with elevated aPTT (37.7sec), normal PT (13.2 sec), normal haptoglobin (236mg/dL) negative coombs test and leukocytosis of 110 x 103/mcL. PTT corrected on mixing study (44 second corrected to 33.8 with 1:1 mixing). Further labs obtained included negative lupus anticoagulant, factors VII (75%), VIII (37%), IX (97%), XI (81%) activity and von Willebrand factor panel (Von Willebrand factor Ag 21%, Factor VIII Activity 37%, Von Willebrand Factor Risocetin Cofactor Activity <10%). His vWF panel was suggestive of Type 2 Von Willebrand disease in the absence of high molecular weight bands. Hospital course was significant for transfusion of 11 units of RBC and repeat endoscopic procedures (Figure 1). Initial upper endoscopy failed to identify a source of hemorrhage. Colonoscopy demonstrated a moderate volume of hematin without evidence of active hemorrhage. Transpyloric pill endoscopy revealed nonspecific hemorrhage throughout the small bowel. Repeat upper endoscopy was performed for continued transfusion requirements with identification of a jejunal angiodysplastic lesion managed with local injection of epinephrine and endoclipping. Despite this intervention, the patient continued to require daily RBC transfusion, necessitating attempted embolization of the gastroduodenal artery. The procedure was aborted due to reversal of conventional directional flow. Given the high transfusion requirement he was initiated on Tranexamic acid and DDAVP for stabilization of the coagulopathy and hemorrhage. A final balloon assisted enteroscopy was significant for two oozing lesions in the gastric cardia, non-bleeding lesions in the lower gastric body, multiple non-bleeding lesions in the third/fourth portion of the duodenum, and the proximal jejunum all consistent with angiodysplasia (Figure 1). Once hemostasis was achieved, induction therapy with Rituximab followed by definitive treatment with rituximab and venetoclax for aVWS secondary to CLL began. Following induction, his leukocytosis markedly improved and gastrointestinal hemorrhage resolved (Figure 2). After discharge, he was followed in the oncology clinic and through six cycles of therapy, he had no recurrence of hemorrhage with resolution of anemia and stabilization of leukocytosis (Figure 2). Prior to cycle 4, Von Willebrand panel was repeated which showed normalization of activity (VWF ristocetin cofactor activity (60%), VWF antigen (67%) and normal factor VIII activity (73%)).