|Year : 2019 | Volume
| Issue : 3 | Page : 823-828
Acquired von Willebrand syndrome: a systemic review
Sabry Shoeib1, Mohamed A El Hafez1, Alaa Efat1, Fatma Noaman2
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
2 Department of Internal Medicine, Shebin El-Kom Teaching Hospital, Shebin El-Kom, Menoufia, Egypt
|Date of Submission||23-Jan-2018|
|Date of Acceptance||06-Mar-2018|
|Date of Web Publication||17-Oct-2019|
Department of Internal Medicine, Ministry of Health, El-Shohada, Menofia Governorate 32717
Source of Support: None, Conflict of Interest: None
The aim was to study the relationship between acquired von Willebrand syndrome (AvWS) and other diseases.
Materials and methods
Medline, Embase, and PubMed databases were searched and also material available in the internet was made use of. The search was performed on 1 May 2016 and included articles published ahead of print with no language restrictions. The search was performed in the electronic databases from 2013 to 2017. The initial search presented 50 articles, papers, and journals. The articles studied the relationship between AvWS and other diseases. Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Owing to the heterogeneity of the causes of AvWS, it was not possible to pool the data and carry out a meta-analysis. Significant data were collected. Thus, a structured review was performed with the results tabulated.
In total, 10 potentially relevant publications were included. The studies indicate the relationship between AvWS and other diseases, such as monoclonal gammopathy of uncertain significance, and lymphoproliferative and myeloproliferative disorders.
Excellent outcomes have been achieved on the topic of AvWS and several diseases such as monoclonal gammopathy of undetermined significance, multiple myeloma, essential thrombocytosis, polycythemia vera, and non-Hodgkin's lymphoma.
Keywords: acquired von Willebrand syndrome, ADAMTS13 metalloproteinase, bleeding disorders, lymphoproliferative, myeloproliferative
|How to cite this article:|
Shoeib S, El Hafez MA, Efat A, Noaman F. Acquired von Willebrand syndrome: a systemic review. Menoufia Med J 2019;32:823-8
| Introduction|| |
Von Willebrand factor (vWF) is a high molecular weight glycoprotein that mediates platelet adhesion at the site of vascular injury, especially under high fluid shear conditions .
The larger vWF multimers are the most hemostatically competent and the loss of these is associated with severe bleeding complications as seen in patients with type 2A von Willebrand disease (vWD) .
vWD is the most commonly inherited bleeding disorder, with an estimated prevalence of 1% of the population .
Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder characterized by structural or functional defects of vWF .
The pathogenic mechanisms include release of autoantibodies against vWF, selective or nonselective absorption, mechanical destruction, increased proteolysis, and decreased synthesis or secretion of vWF .
AvWS usually occurs in association with a variety of underlying disorders, in particular with clonal hematoproliferative diseases, solid tumors, immunological disorders, hypothyroidism, and cardiovascular diseases. Nevertheless, some cases are considered idiopathic, when an underlying disorder cannot be identified .
AvWS is characterized by late onset in individuals with no family or personal history of bleeding .
The aim of this study was to focus on AvWS as a bleeding disorder which is associated with a variety of underlying diseases.
| Materials and Methods|| |
The guideline for conducting this review was according to the guidance developed by the center for review and dissemination. It was used to assess the methodology and outcome of the studies.
We reviewed papers on AvWS from several databases. It included Medline, articles in Medscape, American Academy of Family Physicians and PubMed, and also material available on the internet. We used AvWS and bleeding disorders as the searching terms. The search was performed on electronic databases from 2013 to 2017.
All researches were assessed to include in the review by three researchers. They were included if they fulfilled the following criteria.
Inclusion criteria of the published studies:
- Published in English language
- Published in peer-reviewed journals
- Focused on different causes of AvWS.
Pathophysiology of AvWS.
Hematological disorder and AvWS.
Participants: a review of patients with bleeding disorders evaluated for AvWS.
Intervention: early investigation and management.
Comparative: hematological malignancy such as myeloproliferative and lymphoproliferative neoplasms.
Outcome: proper health.
The article title and abstract were initially screened. Then the selected articles were read in full and further assessed for eligibility. All references from the eligible articles were reviewed in order to identify additional studies.
Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, quantitative results reported for each outcome of interest. Conclusion and comments on each study were made.
There was heterogeneity in the collected data. It was not possible to perform meta-analysis. Significant data were collected. Thus, a structured review was performed with the result tabulated.
The quality of all the studies was assessed. Important factors included, study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, and adequate information and specified assessment measures. It was expected that the confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.
A structured systematic review was performed with the results tabulated.
| Results|| |
A total of 10 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. AvWS is a rare bleeding disorder that occurs in association with a variety of underlying disorders, in particular with monoclonal gammopathy of uncertain significance, lymphoproliferative, myeloproliferative, and neoplastic disorders [Figure 1].
|Figure 1: Pathways to diagnose acquired von Willebrand syndrome according to the reason for test. (a) bleeding disorder (b) AVWS. associated disorders.|
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Relationship between acquired von Willebrand syndrome and monoclonal gammopathy of undetermined significance
Case report studies ,, [Table 1] clarified that patients with AvWS and monoclonal gammopathy of undetermined significance (MGUS) have different options for effective treatment.
|Table 1: Relationship between acquired von Willebrand syndrome and monoclonal gammopathy of undetermined significance|
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Acquired von Willebrand syndrome and multiple myeloma
Case report studies , and one review article  [Table 2] clarified that AvWS is associated with lymphoproliferative disorders such as multiple myeloma.
Acquired von Willebrand syndrome and lymphoma
Case report studies ,,,,, [Table 3] clarified that AvWS is associated with splenic marginal zone lymphoma, mucosa-associated lymphoid tissue lymphoma, and Waldenstrom macroglobulinemia.
| Discussion|| |
According to De Meyer et al. , in 1926, the Finnish hematologist Erik A. von Willebrand described the first patient with a bleeding disorder that now bears his name. The patient was severely affected with multiple episodes of mucosal bleeding that led to her death at the age of 13 years. Four of her 11 siblings were also severely affected. According to Hernndez-Zamora et al. , vWF is a multimeric protein synthetized in cells of the vascular endothelium, megakaryocytes, and platelets with 12 h average life. According to Robertson et al. , vWF is a plasma glycoprotein (Gp); it is calculated that 75–85% of the vWF freely circulating in the plasma is derived from the endothelium, whereas the remaining 15–25% is stored in circulating platelets which originate from the megakaryocyte. According to Wang and colleagues, there are two paths involved in the secretion of vWF. The constitutive path is related to the synthesis of plasma vWF of endothelial origin stored in the Weibel–Palade bodies and the regulated path, which involves the release of vWF fully multimerized, stored in the α granules, in megakaryocytes and platelets. According to Springer , after its release from the cell where it is synthetized, multimers of extremely large and high molecular weight vWF join the endothelial cell surface through interaction with the P-selectin protein of the Weibel–Palade bodies. In this area, vWF multimers are subject to shear stress of the bloodstream, and a physiological reduction of the size of multimers through controlled proteolytic fragmentation, by the ADAMTS13 metalloproteinase. According to James , therefore, the three physiological functions of the protein are: (a) mediating in the adhesion of platelets to areas of vascular damage when joining the GpIb/IX platelet receptor, and collagen in the vascular subendothelium; (b) facilitating platelet aggregation by joining the GpIIb/IIIa platelet receptor; and (c) joining the FVIII and protecting it from proteolytic degradation caused by C protein activated in the bloodstream. According to Lillicrap , vWD is the most common inherited bleeding disorder in humans with prevalence reported in ∼1% of the population. The International Society of Thrombosis and Haemostasis published classification of the vWD in 2006. According to Federici , three main criteria are required for a correct diagnoses of vWD: (a) positive bleeding history since childhood, (b) reduced vWF activity in the plasma, and (c) a history of bleeding in the family with autosomal dominant or autosomal recessive inheritance. According to Waldow et al. , unlike vWD, AvWS is an underdiagnosed and underestimated hemorrhagic disorder that can occur with many different underlying diseases. According to Zoghi et al. , the causes of AvWD are: lymphoproliferative disorders such as MGUS, multiple myeloma, Waldenstrom macroglobulinemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, hairy cell leukemia; myeloproliverative disorders such as essential thrombocythemia, polycythemia vera, and chronic myeloid leukemia; tumors such as Wilm's tumor, Ewing's sarcoma, adrenal cell carcinoma, adenocarcinoma, others; autoimmune disorders such as systemic lupus erythematosus, connective tissue disease, graft vs. host disease; endocrine disorders such as hypothyroidism; cardiovascular disorders and procedures such as congenital cardiac anomalies, mitral valve prolapse, aortic stenosis, ventricular assist devices, heart transplantation, coronary artery bypass surgery, and extracorporeal membrane oxygenation; drugs and therapeutic agents such as antibiotics (ciprofloxacin, levofloxacin, cefotaxime, griseofulvin), anticonvulsants (valproic acid), and recombinant factor hydroxyethyl starch Other causes are uremia, gastrointestinal angiodysplasia, infections (viral, parasitic), Ehlers Danlos syndrome, Gaucher's disease, renal transplantation, autologous stem cell transplantation, lactoferrin deficiency, hemoglobin E-β thalassemia, Turner syndrome, diabetes mellitus. According to Franchini et al. , the pathophysiology of AvWD is complex and not yet entirely understood. There are various proposed mechanisms for AvWD in different underlying diseases. In the majority of cases vWD synthesis in megakaryocytes and endothelial cells is normal or even increased, but there is an accelerated vWF clearance from patients' plasma. The increased vWD clearance is mediated by a variety of mechanisms: presence of autoantibodies against vWF leading to the formation of immune complexes that are removed by macrophages of the reticuloendothelial system (specific anti-vWF autoantibodies with inhibitor function that are directed against GPIb-binding sites in the presence of ristocetin, collagen, αIIbβ3; autoantibodies may also interfere with the assembling of multimers in the vWF molecule, nonspecific antibodies). Adsorption of vWF onto cell's surface (malignant cells, activated platelets) or large molecules (drugs) such as lymphoproliferative diseases or adrenal cell carcinoma by ectopic expression of GPIb or vWF on malignant cells and in essential thrombocythemia large multimers of vWF are adsorbed onto platelets. Increased vWF proteolysis was demonstrated in myeloproliferative diseases, cardiac valve diseases, uremia, and following ciprofloxacin treatment. Mechanical breakage of multimers is secondary to high shear stress in severe aortic stenosis. According to Lippi , AvWS is characterized by late onset in individuals with no family or personal history of bleeding. According to Franchi et al. , clinical symptoms of AvWS are not specific and, like in congenital vWD, include spontaneous skin and mucosal bleeding such as ecchymosis, epistaxis, gingivorrhagia, menorrhagia, gastrointestinal hemorrhage, and postsurgical bleeding. Nonetheless, AvWD diagnosis needs high clinical awareness when consulting adult patients with such hemorrhagic manifestations appearing late in life, in the absence of personal or familial antecedents for coagulation disorders. The role of a careful discussion with patients in order to evaluate bleeding history has to be underlined. A watchful evaluation is needed to identify the underlying conditions potentially associated with AvWD. According to Uriel et al. , distinguishing AvWS and vWD is important because the approaches to treatment can be very different. According to Meyer et al. , we recommend screening for AvWS-associated disorders in all patients with laboratory findings typical of vWD and a negative family history. According to Tiede et al. , the combined interpretation of vWF: Ag, vWF: Ac, and vWF: Rco/vWF: Ag = vWF: Ac/vWF: Ag increases the sensitivity of AvWS diagnosis to a maximum of 86%. According to Federici et al. , additionally, the vWF multimer analysis is still an important diagnostic method in detecting AvWS especially for the detection of structural abnormalities. According to Zoghi et al. , multimer analyses are highly sensitive for predicting vWS even when only slight changes in vWF are presented, but for patients with moderate to severe degradation of vWF, the vWF: RCo/vWF: Ag or vWF: AC/vWF: Ag correlated well with the loss of high molecular weight mannoprotein (HMWM), which applies to the patients with high risk for bleeding. According to Colită et al. , flow cytometric analysis demonstrates absorption of vWF onto the cell surface by detecting ectopic expression of GPIb, αIIbβ3, or other platelet receptors. Mixing tests or enzyme-linked immunosorbent assay are used to reveal anti-VWF autoantibodies. AvWD treatment has two major objectives: according to Stuijver et al. , control of bleeding and therapy or correction (if possible) of the underlying condition. Hemorrhage therapy may employ desmopressin (DDAVP), concentrates containing vWF, recombinant factor VII, antifibrinolytics, 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate, intravenous immunoglobulins (Igs) (in AvWD associated to IgG monoclonal gammopathies), and plasmapheresis (in AvWD associated to IgM monoclonal gammopathies). According to Colită et al. , treatment of the underlying disease may control AvWD's manifestations and is specific for each condition: chemotherapy (lymphoproliferative disorders), cytoreduction (myeloproliferative syndromes), corrective surgery (cardiac valve anomalies), surgery and/or radio-/chemotherapy (solid tumors), immunosuppression (autoimmune disorders), and thyroxin (hypothyroidism).
| Conclusion|| |
VWD is the most commonly inherited bleeding disorder, with an estimated prevalence of 1% of the population. AvWS is a rare bleeding disorder characterized by structural or functional defects of vWF. The pathophysiology of AvWD is complex and not yet entirely understood. There are various proposed mechanisms for AvWD in different underlying diseases. AvWS has been mostly associated with monoclonal gammopathy of uncertain significance, lymphoproliferative, myeloproliferative, and neoplastic disorders, more rarely with hypothyroidism, uremia, pancreatitis, liver cirrhosis, and autoimmune disorders (i.e., systemic lupus erythematosus). Nevertheless, some cases are considered idiopathic, when an underlying disorder cannot be identified. AvWS is characterized by late onset in individuals with no family or personal history of bleeding.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]