Management of a Young Patient With High-risk Multiple Myeloma Complicated by Acquired von Willebrand Syndrome: A Diagnostic and Therapeutic Emergency

Acquired von Willebrand's syndrome type I is the supposed main underlying cause of bleeding tendency in hypothyroid patients. The purpose of this systematic review was to summarize the published evidence on the association between hypothyroidism and acquired von Willebrand's syndrome. All published clinical epidemiological and interventional studies, case reports and in vitro studies that investigated the association between hypothyroidism and acquired von Willebrand's syndrome were identified by a computer-assisted search of the MEDLINE and EMBASE electronic databases. A quality assessment was performed for clinical epidemiological studies. A total of 41 papers were included. A total of 22 epidemiological in vivo studies, two in vitro studies and 47 case reports were finally analyzed. No high quality in vivo study was identified. Almost all bleeding episodes described in the case reports were mucocutaneous. von Willebrand factor (VWF) antigen value was available for 23 patients: median value 28 U/dL (range: 4-45); VWF activity was available for 24 patients: median value 28.5 U/dL (range: <3-55); factor VIII activity was available for 16 patients: median value 47 U/dL (range: 9-74). Acquired von Willebrand's syndrome may be the main factor responsible for bleeding diathesis in overt hypothyroid patients. Even if bleeding episodes are mainly mild and mucocutaneous, blood transfusion, drug administration or surgical procedure may be required.

We report a case of acquired von Willebrand's syndrome with severe gastrointestinal bleeding and associated free monoclonal lambda light chains. The patient had a rapid sustained clinical and laboratory response to the administration of prednisone. Of note in this patient was the occurrence of angiodysplasia which has previously been reported in association with acquired von Willebrand's syndrome. No inhibitors of VWF:Ag, VWF:RCoF, or factor VIII:C were detected by mixing studies and the bleeding time was normal. Very few high molecular weight von Willebrand multimers were present prior to prednisone; however, the pattern reverted to a normal distribution following treatment. In appropriate patients with acquired von Willebrand's syndrome and monoclonal para-proteins, a trial of prednisone may be indicated.

Hypertrophic Obstructive Cardiomyopathy, Acquired von Willebrand Syndrome, and Gastrointestinal Bleeding

Acquired von Willebrand's syndrome is a newly recognized bleeding diathesis thought to be caused by autoantibodies to the von Willebrand factor. Acquired von Willebrand's syndrome has been reported in association with lymphoproliferative disorders and benign monoclonal gammopathies. Clinical features and laboratory abnormalities of this disease are similar to congenital von Willebrand's disease, but the optimal treatment may differ. We describe a 75-year-old man with chronic lymphocytic leukemia and recurrent epistaxis and also discuss the pathogenesis, diagnosis, and treatment of both the congenital and acquired disorders.

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with clinical and laboratory features closely resembling hereditary von Willebrand disease (vWD), arising in previously haemostatically normal individuals. We present a retrospective review of 10 cases with AvWS diagnosed over 17 years. The severity of the bleeding tendency varied from mild to severe forms. Multimers electrophoresis showed that 8/10 patients had a normal pattern similar to type 1 vWD, 1/10 had a type 2A vWD pattern (with absence of high and intermediate molecular weight multimers) and 1/10 had a type 3 vWD pattern. An inhibitor screen was performed in 6/10 patients and autoantibodies against von Willebrand factor were found in only two cases. The underlying cause/associated conditions were identified in 8/10 patients. Treatment of the bleeding diathesis was successfully achieved with desmopressin or clotting factor concentrates. Resolution of underlying hypothyroidism (in two cases) and multiple myeloma (in one case) led to normalization of the coagulation parameters. The report on this cohort of 10 patients with AvWS illustrates the complexity of AvWS and its multifactorial aetiology. A brief review of the recent literature on AvWS is also presented, with emphasis on the current opinions in pathogenesis and treatment. Acquired von Willebrand syndrome (AvWS) is an acquired bleeding disorder, characterized by a phenotype similar to the inherited von Willebrand disease (vWD), with a prolonged bleeding time and low plasma levels of factor VIII - von Willebrand factor (vWF) measurements. It occurs in patients with no family history of vWD, who present with recent onset of bleeding symptoms. AvWS appears to be associated mainly with lymphoproliferative disorders, immunological conditions and neoplasia. AvWS is a rare condition and it is difficult to conduct prospective studies, therefore it is important to document the experience with such cases. The aim of this paper is first, to report 10 cases of AvWS identified at our Haemophilia Centre during the past 17 years. Second, to present a brief review of the recent literature on AvWS - outlining the salient features, associated disorders, mechanisms of acquisition and the available options of treatment.

Diagnostic Workup of Patients with Acquired Von Willebrand's Syndrome.

Are intravenous immunoglobulins really inappropriate in acquired von Willebrand syndrome?

1) Describe the prevalence of acquired von Willebrand syndrome in pediatric patients undergoing extracorporeal membrane oxygenation deemed to be at increased risk for the disease in our institution, 2) discuss the challenges of testing for acquired von Willebrand syndrome diagnosis, 3) describe the characteristics of the patient population found to have acquired von Willebrand syndrome and their outcomes, and 4) discuss the potential implications of acquired von Willebrand syndrome on bleeding complications. Retrospective chart review. PICU and cardiovascular ICU in a single institution. All PICU and cardiovascular ICU extracorporeal membrane oxygenation patients 0-18 years old who underwent screening for acquired von Willebrand syndrome between January 2014 and December 2016. Humate P administration to a small subset of acquired von Willebrand syndrome positive subjects. Laboratory data of identified patients were analyzed. The diagnosis of acquired von Willebrand syndrome was made based on decreased ristocetin cofactor activity to von Willebrand factor antigen ratio and/or abnormal multimer analysis. Clinical data were extracted from the chart and through the Pediatric Extracorporeal Membrane Oxygenation Outcome Registry to describe the demographics, comorbidities, and outcomes of this patient population. In the 2 years, 29 patients had laboratory testing performed for surveillance and in cases of clinical bleeding. Of these, 23 (79%) were positive by criteria. No significant difference in mortality rate was found between patients with acquired von Willebrand syndrome versus without. We also did not find a significant difference in the blood product utilization or bleeding complications between patients with acquired von Willebrand syndrome versus without. Humate P was administered in 39% of patients (9/23) who were positive for acquired von Willebrand syndrome, but no significant difference was seen in blood product utilization or bleeding complications between acquired von Willebrand syndrome patients receiving Humate P versus those who did not. Acquired von Willebrand syndrome is a common but under recognized disorder in pediatric extracorporeal membrane oxygenation patients. The clinical implications of this disorder on bleeding and its potential treatments are still unclear.

Acquired von Willebrand's disease or syndrome (AVWS) is a rare bleeding disorder distinguished from congenital von Willebrand's disease by age at presentation and absence of personal and family history of bleeding disorders. We report on 22 patients with AVWS seen over 25 years. Mean age at diagnosis was 61.3 years (range 38-86 years); most patients had a spontaneous or a post-operative hemorrhage at presentation. Gastrointestinal bleeding and epistaxis were the most common spontaneous symptoms. Bleeding time was prolonged in most patients, associated with marked reductions in plasma von Willebrand factor antigen and ristocetin cofactor activity. Plasma VWF multimer distribution was normal (type 1 pattern) in 5 patients, indeterminate (no multimers detectable) in 6 patients (type 3 pattern), and abnormal (decreased higher-molecular-weight multimers, type 2 pattern) in 11 patients. None of 17 patients tested had an inhibitor of ristocetin cofactor activity. An underlying malignant or benign hematologic disease was found in 18 patients, and 1 patient had Crohn's disease. Desmopressin was effective in only half the patients so treated, but all patients responded to treatment with VWF-containing concentrates. Resolution of AVWS occurred with therapy of lymphoma (1 patient) and chronic lymphocytic leukemia (1 patient). Sixteen patients were alive at last follow-up; no deaths were related to bleeding. AVWS may be more prevalent than has been appreciated; we estimate up to 0.04%. Awareness of the existence of AVWS is essential for diagnosis and appropriate management. Therapy of associated diseases may improve the bleeding disorder.

Acquired von Willebrand syndrome (AvWS) is bleeding disorder that develops de novo in an individual with a negative past personal and family history of bleeding in association with laboratory studies indicative of von Willebrand disease. This diagnosis can be difficult to distinguish from hereditary von Willebrand syndrome, especially in children. Potential mechanisms causing AvWS include decreased protein synthesis, increased proteolysis of mature von Willebrand factor or accelerated clearance of mature vWF(on an immunologic or adsorptive basis). VWF is synthesized in endothelial cells and megakaryocytes as a pre-propolypeptide that undergoes proteolytic cleavage forming the propolypeptide (vWAgII) and mature vWF. These two proteins are immunologically distinct. We hypothesized that since vWAgII has different functional and immunological characteristics from mature vWF, levels of vWAgII should be normal or increased in states of increased vWF clearance or proteolysis. In contrast, levels of vW AgII should parallel those of mature vWF in states of decreased protein synthesis. We studied 24 individuals, 3-79 years of age, referred for evaluation of AvWS. All 24 had reduced levels of vWF antigen, mean 17±3 u/dL. There was a striking difference in vWAgII levels for the 5 individuals with hypothyroidism when compared to all other individuals, mean 55±4 for hypothyroid subjects v. 120±13 u/dL for all other diagnoses (p=.0001). We had previously shown that the ratio of vWF antigen to vWAgII in normal plasma and in plasma from individuals with type 1 von Willebrand disease was unity. This ratio was markedly different between the groups with AvWS, mean vWF/vWAgII for hypothyroid subjects was 0.53±.11 v. 0.14±.04 for other diagnoses (p=.02). In support of the hypothesis that decreased vWF and vWAgII levels in hypothyroidism are secondary to decreased protein synthesis, 4 patients demonstrated normalization of both vWF and vWAgII following thyroid replacement. Although no subject studied had an inhibitor of vWF ristocetin cofactor activity, 3 euthyroid subjects who underwent DDAVP trials demonstrated accelerated clearance of vWF antigen. vWAgII successfully differentiates AvWS caused by decreased synthesis from AvWS due to increased clearance of vWF.

Acquired Von Willebrand Syndrome Associated with B Cell Chronic Lymphoproliferative Disorders. Results from a Prospective Observational Study

Rituximab Use in Four Patients with Acquired vonWillebrand's Syndrome.

A young infant with Wilms' tumour was found to have acquired von Willebrand's syndrome but no bleeding symptoms. Neither parent of the infant had evidence of von Willebrand's syndrome. Postoperatively, after removal of the tumour, factor VIII complex levels returned to normal. The mechanism of the acquired von Willebrand's syndrome was unclear. No evidence was found of an inhibitor of factor VIII complex or entrapment of factor VIII in the tumour.

Dear Sir, I read with interest the letter “Are intravenous immunoglobulins really inappropriate in the acquired von Willebrand syndrome?” by Federici et al1. Intravenous immunoglobulin (IVIG) is a fractionated blood product made from pooled human plasma. It was introduced in the late 1970s and rapidly subsumed the use of intramuscular preparations as replacement therapy in primary and secondary immunodeficiencies. It is increasingly important in replacement therapy and as an immunomodulatory agent in autoimmune disease and transplantation. IVIG is the market driver for the plasma industry in the developed world. The literature on this therapeutic agent increases exponentially and the burgeoning interest in therapeutic immunoglobulin is rapidly generating new evidence, both expanding and reducing current therapeutic indications, with varying levels of supportive evidence. In 1998, the effectiveness of IVIG was demonstrated in an open-label crossover study in patients with acquired von Willebrand syndrome associated with monoclonal gammopathy of uncertain significance of the IgG class2. In 2000, an in ternational registry series reported that one-third of the 63 patients treated with high-dose IVIG had a good response1. The currently limited evidence of the probable benefit of IVIG in the very rare bleeding disorder known as autoimmune acquired von Willebrand disease, though mainly coming from case reports and case series and not from large well-designed, prospective, randomised trials, is continuously growing, also thanks to the international registry of the International Society on Thrombosis and Haemostasis. Despite the low level of evidence case reports and case series can provide us with, they are still part of the evidence hierarchy in evidence-based practice and guide an important part of clinical practice. Case series are incorporated in a significant proportion of health technology assessments3. In 2007, the Australian Health Ministers’ Conference issued the “Criteria for the clinical use of intravenous immunoglobulin in Australia” and suggested that the management of autoimmune acquired von Willebrand syndrome includes the treatment of the underlying medical condition and should be undertaken only by or in consultation with haemophilia treatment centres keeping in mind that IVIG constitutes only part of the management of these complex patients4, who also require additional haemostatic support. This very rare and severe bleeding disorder is one of the conditions for which IVIG use is suggested in exceptional circumstances only. These circumstances include the management of bleeding and prior to invasive procedures, except cases associated with IgM paraprotein in which response is unlikely. The use of IVIG is also indicated in cases of failure to respond to chemotherapy/immunosuppressants or when there is insufficient time for chemotherapy/immunosuppressants to be given. In 2011, the guidelines of the United Kingdom Department of Health also recommended that IVIG treatment in this severe bleeding disorder be only undertaken in a comprehensive care centre for haemophilia. In addition, “IVIG is only recommended for patients with acquired von Willebrand syndrome with life- or limb-threatening haemorrhage who have not responded to other treatments, or prior to invasive procedures (grade B recommendation, level IIa evidence)” 5. For the above reasons, although more research is needed, undoubtedly autoimmune acquired von Willebrand syndrome deserves to be included in the rapidly growing list of non-recognised conditions in which IVIG has been utilised with some benefit, as suggested by Federici et al1.

Lenalidomide as a novel treatment for refractory acquired von Willebrand syndrome associated with monoclonal gammopathy