Continuous-infusion von Willebrand factor concentrate is effective for the management of acquired von Willebrand disease

Acquired von Willebrand disease (aVWD) is a rare disorder associated with a reduction in von Willebrand factor (VWF) activity, leading to increased bleeding risk. Monoclonal gammopathy of undetermined significance (MGUS) is the most common cause of lymphoproliferative disorder-associated aVWD and is caused by accelerated clearance of circulating VWF. Standard VWF replacement protocols for congenital VWD based on intermittent bolus dosing are typically less effective for aVWD because of antibody-mediated clearance. Intermittent bolus dosing of VWF concentrates often leads to inadequate peak response and profoundly shortened VWF half-life in aVWD. Intravenous immune globulin (IVIG) has demonstrated efficacy in aVWD; however, treatment effect is delayed up to 4 days, limiting its efficacy in acutely bleeding patients. We report the successful use of continuous-infusion VWF concentrate (with or without concomitant IVIG) in 3 patients with MGUS-associated aVWD who had demonstrated an inadequate response to bolus dosing. VWF concentrate doses required in this cohort were higher than typical doses for bleeding treatment in congenital VWD. This report illustrates that continuous-infusion VWF concentrate administration with or without intravenous immunoglobulin rapidly achieves target ristocetin cofactor activity and provides adequate hemostasis in aVWD associated with immunoglobulin G MGUS.

Autoimmune- and complement-mediated hematologic condition recrudescence following SARS-CoV-2 vaccination

A variety of autoimmune disorders have been reported after viral illnesses and specific vaccinations. Cases of de novo immune thrombocytopenia (ITP) have been reported after SARS-CoV-2 vaccination, although its effect on preexisting ITP has not been well characterized. In addition, although COVID-19 has been associated with complement dysregulation, the effect of SARS-CoV-2 vaccination on preexisting complementopathies is poorly understood. We sought to better understand SARS-CoV-2 vaccine-induced recurrence of autoimmune- and complement-mediated hematologic conditions. Three illustrative cases were identified at the University of Washington Medical Center and the Seattle Cancer Care Alliance from January through March 2021. We describe the recrudescence of 2 autoimmune conditions (ITP and acquired von Willebrand Disease [AvWD]/acquired hemophilia A) and 1 complementopathy (paroxysmal nocturnal hemoglobinuria [PNH]). We report the first known case of AvWD/acquired hemophilia A, and describe the first PNH exacerbation in the absence of complement inhibition after SARS-CoV-2 vaccination. Although SARS-CoV-2 vaccine-induced ITP is a known concern, our case clearly depicts how thrombocytopenia in the setting of preexisting ITP can sequentially worsen with each vaccine dose. Based on our experiences and these examples, we provide considerations for how to monitor and assess risk in patients with underlying autoimmune- and complement-mediated hematologic conditions.

The pathobiology of thrombosis, microvascular disease, and hemorrhage in the myeloproliferative neoplasms

Thrombotic, vascular, and bleeding complications are the most common causes of morbidity and mortality in the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In these disorders, circulating red cells, leukocytes and platelets, as well as some vascular endothelial cells (ECs), each have abnormalities that are cell-intrinsic to the MPN driver mutations they harbor (e.g. JAK2 V617F). When these cells are activated in the MPNs, their interactions with each other create a highly pro-adhesive and prothrombotic milieu in the circulation that predisposes MPN patients to venous, arterial, and microvascular thrombosis and occlusive disease. Bleeding problems in the MPNs are caused by the MPN blood cell-initiated development of acquired von Willebrand disease. The inflammatory state created by MPN stem cells in their microenvironment extends systemically to amplify the clinical thrombotic tendency and, at the same time, preferentially promote further MPN stem cell clonal expansion, thereby generating a vicious cycle that favors a prothrombotic state in these diseases.

Gastrointestinal Bleeding in the Setting of Left Ventricular Assist Device Support

In this chapter, the authors discuss the pathophysiology, diagnosis, and treatment of gastrointestinal bleeding (GIB) in the setting of left ventricular assist device (LVAD) support. Briefly, LVAD surgery has become widespread. Despite numerous advances, LVADs continue to be associated with a high incidence of GIB. The pathophysiology of this is multifactorial, with contributors including acquired von Willebrand disease and angiodysplasia. When GIB is suspected, it is imperative to consult a gastroenterologist and cardiologist. Endoscopy is the principal diagnostic and therapeutic modality. Occult GIB may be investigated with enteroscopy, capsule endoscopy, and angiography. Pharmacologic treatment may include a brief hold of anticoagulation and initiation of angiotensin-converting enzyme inhibitors, proton pump inhibitors, and octreotide, among other drugs. Evidence for pharmacotherapy, however, is limited. At the time of discharge, the focus should be on secondary prevention. In summary, LVAD-related GIB is a unique clinical problem that requires multimodal and multidisciplinary management.

How I treat gastrointestinal bleeding in congenital and acquired von Willebrand disease

Gastrointestinal (GI) bleeding is distinctive of severe von Willebrand disease (VWD), generally arising in older patients; in most cases, blood transfusion and hospitalization are required. The presence of arteriovenous malformations is often described when endoscopic examinations are performed. Patients with congenital type 3, 2A, and 2B are those most frequently affected by this symptom, possibly due to the loss of high-molecular-weight multimers of von Willebrand factor (VWF). GI bleeding can also occur in patients affected by acquired von Willebrand syndrome. Endoscopic examination of the GI tract is necessary to exclude ulcers and polyps or cancer as possible causes of GI bleeding. In congenital VWD, prophylaxis with VWF/factor VIII concentrates is generally started after GI-bleeding events, but this therapy is not always successful. Iron supplementation must be prescribed to avoid chronic iron deficiency. Possible rescue therapies (high-dose statins, octreotide, thalidomide, lenalidomide, and tamoxifen) were described in a few case reports and series; however, surgery may be necessary in emergency situations or if medical treatment fails to stop bleeding. In this article, we present several clinical cases that highlight the clinical challenges of these patients and possible strategies for their long-term management.