Identification of acquired von Willebrand syndrome (AVWS) was key to treating a patient with chronic gastrointestinal (GI) bleeding due to angiodysplasia. After exhausting endoscopic and pharmacological options, the patient was successfully treated with rituximab. A 78-year-old man developed chronic GI bleeding from caecal and jejunal angiodysplasia. Red cell transfusion was required weekly despite argon plasma coagulation. A diagnosis of AVWS was made from analysis of clotting factors. Therapies including von Willebrand factor concentrate, thalidomide and tranexamic acid were unsuccessful. With failed endoscopic therapy and no viable surgical option, the patient was given intravenous immunoglobulins (IVIGs). Haemoglobin remained stable from this point. The impact on the patient and hospital of attending for IVIG every 3 weeks necessitated consideration to longer-term therapy. After a single course of rituximab, no further blood products, IVIG or rituximab were required. This case is the first to describe the use of rituximab in AVWS-associated angiodysplasia.
- gastrointestinal bleeding
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Angiodysplasia is the most common cause of obscure gastrointestinal (GI) bleeding in the elderly. Endoscopic destruction using non-contact techniques, such as argon plasma coagulation (APC), are most often proposed as first-line treatment, followed by pharmacological therapies such as somatostatin analogues, oestroprogestative agents and thalidomide. High rebleed rates despite endoscopic therapy have been attributed to other areas of angiodysplasia rather than failure of obliteration. Risk factors for recurrence are multiple lesions, increasing age and clotting abnormalities. There is a well-documented link between angiodysplasia and acquired von Willebrand syndrome (AVWS).
AVWS most often arises in the seventh decade of life in patients without prior bleeding history. Patients often present to acute medical or surgical teams, so it is essential these groups are aware of this rare but treatable condition. At present, the incidence is underestimated as it often goes undiagnosed.
AVWS is an uncommon bleeding disorder that, by definition, is not inherited. Accelerated removal of von Willebrand factor (VWF) from plasma compromises its two critical functions: facilitation of platelet binding at sites of injury and carrier of factor VIII in the circulation.1 There are a number of pathological mechanisms: autoantibodies, sequestration of heavyweight multimers and shear stress–induced unfolding. It has recently been discovered that VWF may have a role in regulating blood vessel formation, illustrating a direct link between AVWS and angiodysplasia.2 Loss of VWF can result in dysfunctional angiogenesis.
It is often associated with underlying haematological, autoimmune or neoplastic disease, in addition to structural abnormalities, such as aortic valve stenosis. Bleeding will often first present following trauma or surgery, but bleeding from mucous membranes, GI and genitourinary tracts is also characteristic.3 A clotting screen will often demonstrate a prolonged activated partial thromboplastin time (APTT) due to reduced factor VIII, but a normal clotting screen does not rule out the diagnosis. A series of specific laboratory tests may be required. Goals of treatment are control of bleeding, prevention of bleeding and management of the underlying cause. Treatment is patient specific and can involve use of VWF replacement, desmopressin, immunoglobulins, plasmapheresis and immunosuppressive agents. Depending on the underlying cause, patients may require valvular surgery or chemotherapy. Diagnosis and management should involve a haematology clinician with an interest in haemostasis.
The patient described here had chronic GI bleeding requiring weekly transfusions, despite endoscopic and conventional medical therapy. The case highlights the relevant investigations for GI bleeding and the link between angiodysplasia and AVWS, as well as drawing attention to a novel therapeutic option.
A 78-year-old man presented to hospital with melena and initial Hb 71 g/dL. Pre-endoscopy Glasgow Blatchford Score of 9 suggested in-hospital intervention was necessary.
The patient was fluid resuscitated, including transfusion with 2 units of blood. Initial oesophagogastroduodenoscopy (OGD) and contrast CT scan were unremarkable. The melena resolved and with stable haemoglobin he was discharged with a plan for outpatient colonoscopy. However, he was soon readmitted with melena. Repeat OGD was normal and subsequent inpatient colonoscopy identified non-bleeding caecal angiodysplasia, treated unsuccessfully with APC (figure 1). No source of bleeding was found on CT angiogram.
The patient continued to require frequent blood transfusions, which were organised as an outpatient with further inpatient admissions avoided. Capsule endoscopy showed jejunal angiodysplasia with fresh bleeding (figure 2), prompting an urgent double-balloon enteroscopy. There was no drop in transfusion requirement despite APC to the jejunal angiodysplasia. Surgery was discounted due to his significant comorbidities and multiple potential bleeding sites.
A clotting screen identified prolonged APTT raising the possibility of a bleeding disorder. Further investigations revealed significantly reduced quantity and function of VWF along with low factor VIII (table 1). Consultation with a haematologist confirmed the diagnosis of AVWS. Trials of VWF concentrate and thalidomide (100 mg/day for 1 month, 200 mg/day for 1 month) were given without benefit. After treatment with intravenous immunoglobulin (IVIG), there was no further bleeding. IVIG was given every 3 weeks, necessitating attention to longer-term therapy.
Rituximab was given 375 mg/m2 weekly for 4 weeks with successful response. His levels of VWF antigen, VWF Ristocetin Cofactor (RCo) and factor VIII were monitored fortnightly and remained normal 3 months after rituximab. No more IVIG was needed. This might be opening a new era for diagnosing and treating chronic GI bleed in the context of AWVS.
This case was initially managed with red cell transfusion. Tranexamic acid was trialled without benefit. Due to the presence of an angiodysplasia, noted during colonoscopy, a diagnosis of Heyde’s syndrome was considered. This is associated with aortic stenosis or the presence of left ventricular assist devices (LVADs). High shear stress results in unfolding and cleavage of VWF. An echocardiogram discounted this possibility. However, an association between exaggerated bleeding from angiodysplasia of the GI tract and pathologically low VWF in the absence of valvular disease/LVAD is also recognised. In vitro and in vivo studies have indicated that VWF has a role in regulating angiogenesis through various pathways.2 Problematic GI bleeding in patients with AVWS due to immunogenic causes who are refractory to conventional therapies have been successfully managed with thalidomide, most likely due to the antiangiogenic properties.4
A trial of VWF concentrate failed to demonstrate a clinically significant rise in the VWF plasma concentration in this case. In one case series of 25 patients, 20 responded to VWF replacement (80%).3 Second-line therapy with IVIG was rapidly effective in stopping further GI bleeding although response was short-lived (5–6 weeks) and more definitive therapy was necessary. Rituximab was given 375 mg/m2 weekly for 4 weeks with successful response (figure 3). VWF:Ag, VWF:RCo and factor VIII were monitored fortnightly and remained normal 3 months after rituximab. No more IVIG was needed.
Rituximab is an anti-CD20 monoclonal antibody that is commonly used to treat autoimmune conditions. Mature B lymphocytes are among other things responsible for antibody production, and all express CD20 on their cell surface. Reduction of B lymphocytes by targeting CD20 reduces the amount of antibody produced and its effect.
The patient was thoroughly investigated for underlying disorders that are known to be associated with emergence of autoimmune conditions such as solid malignancies, lymphoproliferative disorders and monoclonal gammopathy. This included a CT scan, bone marrow biopsy, autoimmune screen and serum electrophoresis. As these investigations, along with the echocardiogram, failed to demonstrate any additional pathology, it was concluded that the patient had a primary autoimmune cause for the AVWS. This was supported by a rapid improvement in response to IVIG and rituximab.
Outcome and follow-up
Regular blood tests showed no further evidence of bleeding. After follow-up 6 months after rituximab, the patient was discharged.
The effectiveness of IVIG has been demonstrated in terms of increasing VWF measurements and shortening bleeding time. Rituximab for AVWS is less well recognised and was first described in 2006 in four cases of AVWS-associated IgG monoclonal gammopathy of undetermined significance.5 A handful of other cases have described its use for perioperative bleeds. To the best of our knowledge, there are no published reports on its use in treating bleeding angiodysplasia.
Angiodysplasia is a common cause of obscure gastrointestinal bleeding, with significant risk of rebleeding.
It is important to consider clotting factor abnormalities and deficiencies in patients with chronic gastrointestinal bleeding.
Intravenous immunoglobulin and rituximab can be a rapid and effective treatment for patients with chronic gastrointestinal bleeding due to acquired von Willebrand syndrome.
Contributors JH wrote the abstract, case summary, discussion and learning points. AK conducted a literature search and wrote the discussion and treatment sections. WA wrote and edited sections of the revised manuscript. AC and FF edited and critically appraised the case report. FF is responsible for the overall content.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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